Asymmetric synthesis catalyst based on chiral brsnsted acid and method of asymmetric synthesis with the catalyst

ABSTRACT

A compound usable as an asymmetric synthesis catalyst which can be easily synthesized without using any metal such as a lanthanoid group element; a method of asymmetric synthesis with the compound; and a chiral compound obtained by the asymmetric synthesis method. A Broensted acid is used as a catalyst in asymmetric synthesis, the chiral Broensted acid being represented by formula (1) below or formula (3) below. The asymmetric synthesis method employs the catalyst. Asymmetric synthesis with the catalyst gives a chiral compound.

TECHNICAL FIELD

The present invention relates to a catalyst for use in asymmetricsynthesis, and a method of asymmetric synthesis using the catalyst.Chiral compounds obtained by the method of the present invention areuseful as compounds used in pharmaceuticals, agrochemicals, etc., orsynthetic intermediates therefor.

BACKGROUND ART

A Diels-Alder cyclization reaction using a metal salt of a chiralbinaphthol-phosphoric acid derivative is known (e.g. JP-A-2000-336097;JP-A denotes a Japanese unexamined patent application publication), butthere is no known asymmetric synthesis method using a chiralbinaphthol-phosphoric acid derivative that is not a metal salt, namely,a chiral Broensted acid. Furthermore, a chiral compound has beensynthesized by carrying out an asymmetric Mannich reaction using achiral urea derivative (ref., e.g. Anna G. Wenzel et al., “AsymmetricCatalytic Mannich Reactions Catalyzed by Urea Derivatives:Enantioselective Synthesis of β-Aryl-β-Amino Acids”, Journal of TheAmerican Chemical Society, 124, 12964-5 (2002)).

DISCLOSURE OF INVENTION

Some conventional methods of asymmetric synthesis, such as an asymmetricMannich reaction and an asymmetric aza Diels-Alder reaction, can give aproduct with high optical purity, but in these reactions it is essentialto use a metal such as a lanthanoid group element. Under suchcircumstances, it is to provide a compound that can be used as anasymmetric synthesis catalyst that enables the synthesis to be carriedout easily without using a metal such as a lanthanoid group element, amethod of asymmetric synthesis using said compound, and a chiralcompound obtained by said method of asymmetric synthesis.

In order to solve the above-mentioned problems, the present inventor hascarried out an intensive investigation into the development of anasymmetric synthesis catalyst that can be used under practical reactionconditions and gives high optical purity. As a result, it has been foundthat by the use of a chiral Broensted acid as a catalyst a compoundhaving high optical purity can be synthesized, and the present inventionhas thus been accomplished. This chiral Broensted acid is a chiralbinaphthol-phosphoric acid derivative and is, for example, a chiralbinaphthol-phosphoric acid derivative represented by formula (1) belowor formula (3) below. The present invention is also a method ofasymmetric synthesis using the chiral Broensted acid as a catalyst.

In formula (1) above, R₁, R₂, R₃, and R₄ may be independent of eachother, and denote a hydrogen atom; a halogen atom; a nitro group; amonohalogenomethyl group; a dihalogenomethyl group; a trihalogenomethylgroup; a nitrile group; a formyl group; —COA₁ (A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons); —COOA₂ (A₂ denotes anoptionally branched alkyl group having 1 to 6 carbons); an optionallybranched alkyl group. having 1 to 20 carbons; an optionally branchedalkenyl group having 3 to 20 carbons; an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group; an aryl group mono- ordi-substituted with an aryl group; an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁ (A₁ denotes an optionally branched alkyl grouphaving 1 to 6 carbons), —COOA₂ (A₂ denotes an optionally branched alkylgroup having 1 to 6 carbons), an optionally branched alkyl group having1 to 10 carbons, an optionally branched alkenyl group having 1 to 10carbons, and an optionally branched alkoxy group having 1 to 20 carbons;an aryl group mono- or di-substituted with an aryl group that may bemono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁ (A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons), —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons), and an optionally branched alkylgroup having 1 to 20 carbons; a cycloalkyl group having 3 to 8 carbons;or formula (2) below.

A₃, A₄, and A₅ of formula (2) may be independent of each other, anddenote an optionally branched alkyl group having 1 to 6 carbons, aphenyl group, or a phenyl group mono- to tetra-substituted with anoptionally branched alkyl group having 1 to 6 carbons.

In formula (3), R₁ and R₂ may be independent of each other, and denote ahydrogen atom; a halogen atom; a nitro group; a monohalogenomethylgroup; a dihalogenomethyl group; a trihalogenomethyl group; a nitrilegroup; a formyl group; —COA₁ (A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons); —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons); an optionally branched alkyl grouphaving 1 to 20 carbons; an optionally branched alkenyl group having 3 to20 carbons; an optionally branched alkoxy group having 1 to 20 carbons;an aryl group; an aryl group mono- or di-substituted with an aryl group;an aryl group mono- to tetra-substituted with at least one type selectedfrom the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁ (A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons), —COOA₂ (A₂ denotes anoptionally branched alkyl group having 1 to 6 carbons), an optionallybranched alkyl group having 1 to 10 carbons, an optionally branchedalkenyl group having 1 to 10 carbons, and an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group mono- or di-substituted withan aryl group that may be mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁ (A₁denotes an optionally branched alkyl group having 1 to 6 carbons),—COOA₂ (A₂ denotes an optionally branched alkyl group having 1 to 6carbons), and an optionally branched alkyl group having 1 to 20 carbons;a cycloalkyl group having 3 to 8 carbons; or formula (2).

The present invention is a method of asymmetric synthesis using as acatalyst a compound of formula (1) or formula (3).

The present invention is a chiral compound obtained by a method ofasymmetric synthesis using as a catalyst a chiral Broensted acid, achiral binaphthol-phosphoric acid derivative, or a compound of formula(1) or formula (3).

The present invention is a method for producing a chiral amino compoundfrom an imine derivative and an enol derivative using as a catalyst achiral Broensted acid, a chiral binaphthol-phosphoric acid derivative,or a compound of formula (1) or formula (3).

The present invention is a chiral amino compound obtained by theabove-mentioned production method.

The present invention is an asymmetric Mannich reaction using as acatalyst a compound of formula (1) or formula (3).

The present invention is an asymmetric hydrophosphorylation reactionusing as a catalyst a compound of formula (1) or formula (3).

The present invention is an asymmetric aza Diels-Alder reaction using asa catalyst a compound of formula (1) or formula (3).

The present invention is an asymmetric allylation reaction using as acatalyst a compound of formula (1) or formula (3).

The present invention is an asymmetric Strecker reaction using as acatalyst a compound of formula (1) or formula (3).

The present invention is an asymmetric aminoalkylation reaction using asa catalyst a compound of formula (1) or formula (3).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in detail below. In the explanationbelow, iso- is abbreviated to ‘i-’ and tert- to ‘t-’, etc., and ‘n-’ isbasically omitted.

Chiral Broensted Acid Derivative

Examples of a chiral Broensted acid derivative that can be employed inthe method of asymmetric synthesis of the present invention include achiral binaphthol-phosphoric acid derivative represented by formula (1)above, that is, an R-form binaphthol-phosphoric acid derivative or anS-form binaphthol-phosphoric acid derivative. That is, formula (1)denotes the R-form or the S-form. This derivative can be synthesizedfrom R-form or S-form 1,1′-binaphthyl-2,2′-diol. Formula (1) can besynthesized by referring to a synthetic method described in, forexample, JP-A-47-30617, JP-A-2000-336097, or U.S. Pat. No. 3,848,030.Formula (3) can also be synthesized by referring to these publications.

The synthesis of formula (1) involves, for example, protecting hydroxylgroups of R-form or S-form 1,1′-binaphthyl-2,2′-diol, then producing a3-position, 3′-position, 6-position, and/or 6′-position halogenderivative, then introducing a substituent by a cross-coupling reaction,etc., and carrying out a phosphorylation by reaction with phosphorusoxychloride, etc. As the halogen of this halogen derivative, a chlorineatom, a bromine atom, or an iodine atom is preferable, and a bromineatom or an iodine atom is more preferable.

The position of the halogen derivative at which the halogen atom isbonded is, for example, the 3-position, 3,3′-positions, 6-position,3,6′-positions, 6,6′-positions, 3,3′,6-positions, 3,6,6′-positions, or3,3′,6,6′-positions, preferably the 3,3′-positions, 3,6′-positions,6,6′-positions, 3,3′,6-positions, or 3,3′,6,6′-positions, and morepreferably the 3,3′-positions, 3,3′,6-positions, or 3,3′,6,6′-positions.These bonding positions for the halogen atom also apply to the bondingpositions of the substituents in formula (1). Furthermore, these bondingpositions also basically apply to the bonding positions of thesubstituents in formula (3).

Substituents of Formula (1)

R₁, R₂, R₃, and R₄ of formula (1) may independently be hydrogen atoms,not all of R₁, R₂, R₃, and R₄ are hydrogen atoms, and it is notpreferable for R₁ and/or R₂ to be hydrogen atoms. From this, R₁, R₂, R₃,and R₄ of formula (1) preferably may independently denote a hydrogenatom (not all of R₁, R₂, R₃, and R₄ are hydrogen atoms); a halogen atom;a nitro group; a monohalogenomethyl group; a dihalogenomethyl group; atrihalogenomethyl group; a nitrile group; a formyl group; —COA₁; —COOA₂;an optionally branched alkyl group having 1 to 20 carbons; an optionallybranched alkenyl group having 3 to 20 carbons; an optionally branchedalkoxy group having 1 to 20 carbons; an aryl group; an aryl group mono-or di-substituted with an aryl group; an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, an optionally branched alkyl group having 1to 10 carbons, an optionally branched alkenyl group having 1 to 18carbons, and an optionally branched alkoxy group having 1 to 20 carbons;an aryl group mono- or di-substituted with an aryl group that may bemono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁, —COOA₂, and an optionally branched alkylgroup having 1 to 20 carbons; a cycloalkyl group having 3 to 8 carbons;or formula (2) below.

Examples of the halogen atom bonded to R₁, R₂, R₃, and/or R₄ of formula(1) include a fluorine atom, a chlorine atom, a bromine atom, or aniodine atom, a plurality of types may be bonded simultaneously, and itis preferably a fluorine atom, a chlorine atom, or a bromine atom, andmore preferably a chlorine atom or a bromine atom.

Examples of the halogen atom of the monohalogenomethyl group, thedihalogenomethyl group, or the trihalogenomethyl group bonded to R₁, R₂,R₃, and/or R₄ of formula (1) include a fluorine atom, a chlorine atom, abromine atom, or an iodine atom, and it is preferably a fluorine atom, achlorine atom, or a bromine atom, and more preferably a fluorine atom ora chlorine atom. Those having many halogen atoms bonded thereto arepreferable. That is, a trifluoromethyl group or a trichloromethyl groupare preferable.

A₁ of the —COA₁ bonded to R₁, R₂, R₃, and/or R₄ of formula (1) denotesan optionally branched alkyl group having 1 to 6 carbons, and ispreferably a methyl group or an ethyl group, and more preferably amethyl group.

A₂ of the —COOA₂ bonded to R₁, R₂, R₃, and/or R₄ of formula (1) denotesan optionally branched alkyl group having 1 to 6 carbons, and ispreferably a methyl group, an ethyl group, or a propyl group, and morepreferably an ethyl group.

The optionally branched alkyl group having 1 to 20 carbons bonded to R₁,R₂, R₃, and/or R₄ of formula (1) preferably has 2 to 18 carbons, andmore preferably 4 to 16 carbons. Specific examples thereof include amethyl group, an ethyl group, a propyl group, an i-propyl group, a butylgroup, an i-butyl group, a t-butyl group, a pentyl group, an i-pentylgroup, a hexyl group, an i-hexyl group, an octyl group, an i-octylgroup, a nonyl group, a decyl group, a dodecyl group, a tetradecylgroup, and a hexadecyl group. It is preferably a t-butyl group, a pentylgroup, a hexyl group, or an octyl group.

The optionally branched alkenyl group having 3 to 20 carbons bonded toR₁, R₂, R₃, and/or R₄ of formula (1) preferably has 3 to 18 carbons, andmore preferably 4 to 16 carbons. Specific examples thereof include abutenyl group, a pentenyl group, a hexenyl group, a heptenyl group, anoctenyl group, a nonenyl group, a decenyl group, a dodecenyl group, atetradecenyl group, and a hexadecenyl group. It is preferably a butenylgroup, a pentenyl group, a hexenyl group, a heptenyl group, or anoctenyl group.

The optionally branched alkoxy group having 1 to 20 carbons bonded toR₁, R₂, R₃, and/or R₄ of formula (1) preferably has 1 to 18 carbons, andmore preferably 4 to 16 carbons. Specific examples thereof include amethoxy group, an ethoxy group, a propoxy group, a butoxy group, apentyloxy group, an i-pentyloxy group, a hexyloxy group, an i-hexyloxygroup, an octyloxy group, an i-octyloxy group, a nonyloxy group, adecyloxy group, a dodecyloxy group, a tetradecyloxy group, and ahexadecyloxy group. It is preferably a butoxy group, a pentyloxy group,a hexyloxy group, or an octyloxy group.

Examples of the aryl group bonded to R₁, R₂, R₃, and/or R₄ of formula(1) include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, aphenanthryl group; and an anthryl group, and it is preferably a phenylgroup, a 1-naphthyl group, or 2-naphthyl group.

Examples of R₁, R₂, R₃, and/or R₄ of formula (1) include an aryl groupmono- or di-substituted with an aryl group. Examples of the former arylgroup include a phenyl group, a naphthyl group, a phenanthryl group, andan anthryl group, and it is preferably a phenyl group or a naphthylgroup; examples of the aryl group bonded to the aryl group include aphenyl group, a naphthyl group, a phenanthryl group, and an anthrylgroup, and it is preferably a phenyl group or a naphthyl group.

Specific examples thereof include a biphenyl group, a naphthylphenylgroup, a phenylnaphthyl group, and a naphthylnaphthyl group.

Examples of R₁, R₂, R₃, and/or R₄ of formula (1) include an aryl groupmono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁ (A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons), —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons), an optionally branched alkyl grouphaving 1 to 10 carbons, an optionally branched alkenyl group having 1 to10 carbons, and an optionally branched alkoxy group having 1 to 20carbons.

The alkyl group bonded to the aryl group preferably has 1 to 10 carbons,and more preferably 1 to 6 carbons. Specific examples thereof include amethyl group, an ethyl group, a propyl group, and a butyl group.Examples of this aryl group include a tolyl group, a xylyl group, amesityl group, a methylnaphthyl group, a dimethylnaphthyl group, and amethylanthryl group. It is preferably a tolyl group, a xylyl group, amesityl group, or a methylnaphthyl group.

The alkenyl group bonded to the aryl group preferably has 3 to 18carbons, and more preferably 4 to 16 carbons. Specific examples thereofinclude a butenyl group, a pentenyl group, a hexenyl group, a heptenylgroup, an octenyl group, a nonenyl group, a decenyl group, a dodecenylgroup, a tetradecenyl group, and a hexadecenyl group. It is preferably abutenyl group, a pentenyl group, a hexenyl group, a heptenyl group, oran octenyl group.

The alkoxy group bonded to the aryl group preferably has 1 to 12carbons, and more preferably 1 to 6 carbons. Specific examples thereofinclude a methoxy group, an ethoxy group, a propoxy group, an i-propoxygroup, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxygroup, an i-pentyloxy group, a hexyloxy group, and an i-hexyloxy group.It is preferably a methoxy group, an ethoxy group, or a propoxy group.

The substituent bonded to the aryl group is mono- to tetra-substitutedwith at least one type selected from the group consisting of a nitrogroup, a halogen atom, a monohalogenomethyl group, a dihalogenomethylgroup, a trihalogenomethyl group, a nitrile group, a formyl group, —COA₁(A₁ denotes an optionally branched alkyl group having 1 to 6 carbons),and —COOA₂ (A₂ denotes an optionally branched alkyl group having 1 to 6carbons), and is preferably mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, and a nitrile group. Specific examples of thearyl group include derivatives of a phenyl group to which is bonded ap-nitrophenyl group, a m-nitrophenyl group, an o-nitrophenyl group, a2,4-dinitrophenyl group, a p-fluorophenyl group, a m-fluorophenyl group,an o-fluorophenyl group, a 3,5-difluorophenyl group, a3,4,5-trifluorophenyl group, a 2,4,6-trifluorophenyl group, ap-chlorophenyl group, a m-chlorophenyl group, an o-chlorophenyl group, a3,5-dichlorophenyl group, a 3,4,5-trichlorophenyl group, a2,4,6-trichlorophenyl group, a p-bromophenyl group, a m-bromophenylgroup, an o-bromophenyl group, a 3,5-dibromophenyl group, ap-trifluoromethylphenyl group, a m-trifluoromethylphenyl group, ano-trifluoromethylphenyl group, a p-trichloromethylphenyl group, am-trichloromethylphenyl group, an o-trichloromethylphenyl group, a3,5-di(trifluoromethyl)phenyl group, a 3,5-di(trichloromethyl)phenylgroup, a p-cyanophenyl group, a m-cyanophenyl group, an o-cyanophenylgroup, etc. Furthermore, with regard to a 1-naphthyl group and a2-naphthyl group, those having the same substituents as above can becited as examples.

Examples of R₁, R₂, R₃, and/or R₄ of formula (1) include an aryl groupmono- or di-substituted with an aryl group that may be mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁ (A₁ denotes an optionally branched alkyl grouphaving 1 to 6 carbons), —COOA₂ (A₂ denotes an optionally branched alkylgroup having 1 to 6 carbons), and an optionally branched alkyl grouphaving 1 to 20 carbons.

As the aryl group that may be mono- to tetra-substituted, an aryl grouphaving the above-mentioned substituent can be used, and preferredexamples are the same as above. Among the aryl groups mono- ordi-substituted with the aryl group having the substituent, amono-substituted aryl group is preferable.

Preferred examples of the cycloalkyl group having 3 to 8 carbons in R₁,R₂, R₃, and/or R₄ of formula (1) include a cyclobutyl group, acyclopentyl group, a cyclohexyl group, and a cyclooctyl group. It ispreferably a cyclopentyl group or a cyclohexyl group.

Examples of formula (2) denoted by R₁, R₂, R₃, and/or R₄ of formula (1)include a triphenylsilyl group, a trimethylsilyl group, adimethylethylsilyl group, a triethylsilyl group, a triisopropylsilylgroup, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and adiphenylmethylsilyl group. It is preferably a triphenylsilyl group, atrimethylsilyl group, or a diphenylmethylsilyl group.

Although examples of R₁, R₂, R₃, and R₄ in formula (1) are describedabove, it is preferable for the chiral Broensted acid to have anelectron-attracting group such as a nitro group or a trifluoromethylgroup bonded thereto for use in a method of asymmetric synthesis of thepresent invention. Examples of such an electron-attracting group includea nitro group, a halogen atom, a monohalogenomethyl group, adihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁ (A₁ denotes an optionally branched alkyl grouphaving 1 to 6 carbons), and —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons), and preferred examples thereofinclude a nitro group, a halogen atom, a monohalogenomethyl group, adihalogenomethyl group, a trihalogenomethyl group, a nitrile group, anda formyl group. Examples of the halogen atom of the monohalogenomethylgroup, the dihalogenomethyl group, or the trihalogenomethyl groupinclude a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom, and it is preferably a fluorine atom, a chlorine atom, or abromine atom, and more preferably a fluorine atom or a chlorine atom.Furthermore, A₁ of —COA₁ denotes an optionally branched alkyl grouphaving 1 to 6 carbons, and is preferably a methyl group or an ethylgroup, and more preferably a methyl group. Furthermore, —COOA₂ may be anester group to which an alkyl group having 1 to 6 carbons is bonded, andis preferably an ethyl ester group.

R₁, R₂, R₃, and R₄ of formula (1) in the present invention arepreferably an aryl group to which an electron-attracting group isbonded, more preferably a phenyl group to which an electron-attractinggroup is bonded, and particularly preferably a phenyl group to which anitro group, a halogen atom, a monohalogenomethyl group, adihalogenomethyl group, a trihalogenomethyl group, a nitrile group, or aformyl group is bonded. A plurality of these electron-attracting groupsmay be bonded. It is preferable that an aryl group havingelectron-attracting groups such as a nitro group or a trifluoromethylgroup is bonded to R₁ and R₂. In addition, the electron-attracting groupbonded to the aryl group is preferably bonded at a position in whichelectron attracting properties are exhibited.

Those to which a substituent is bonded in formula (1) are R₁, R₂, R₃,and R₄, and R₁ and R₂ are preferable.

As R₁ and R₂ of formula (3) in the present invention, those cited asexamples in the explanation of formula (1) can be used.

As the asymmetric synthesis catalyst in the present invention, it ispreferable to use a compound represented by formula (1).

A chiral Broensted acid represented by formula (1) or formula (3) usedin the asymmetric synthesis may be in the form of a salt as long as itcan be used as an acid catalyst.

Examples of the chiral binaphthol-phosphoric acid derivative used in thepresent invention are listed below. The compounds illustrated below arethe R-form or the S-form, but their notation is omitted. That is,(R)-3,3′-bis(4-nitrophenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid and(S)-3,3′-bis(4-nitrophenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid areexpressed as 3,3′-bis(4-nitrophenyl)-1,1′-binaphthyl-2,2′-diylphosphoricacid.

Examples of the chiral binaphthol-phosphoric acid derivative include3,3′-dimethyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diethyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dipropyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diisopropyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dibutyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-di-t-butyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dipentyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dihexyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dicyclohexyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diheptyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dioctyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dinonyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-didecyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diphenyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(4-methylphenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(2,6-dimethylphenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diethynyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,6,6′-diethenyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-dioctenyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,6,6′-diethynyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-diethynyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,6,6′-diethenyl-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(triphenylsilyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(mesityl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(4-biphenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(2-naphthyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(2′,4′,6′-trimethylbiphenyl-4-yl))-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis(4-naphthalen-2-yl-phenyl)-1,1′-binaphthyl-2,2′-diylphosphoricacid, 3,3′-bis(4-methoxyphenyl)-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis(4-trifluoromethylphenyl)-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis[3,5-di(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis(4-trichloromethylphenyl)-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis[3,5-di(trichloromethyl)phenyl]-1,1′-binaphthyl-2,2′-diylphosphoricacid, 3,3′-bis(4-nitrophenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(3,5-dinitrophenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid,3,3′-bis(4-cyanophenyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid, and6,6′-dibromo-3,3′-diphenyl-1,1′-binaphthyl-2,2′-diylphosphoric acid.

The substituents at the 3,3′-positions of the compounds represented byformula (1) can be applied to those of formula (3). Examples thereofinclude3,3′-bis(4-trifluoromethylphenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis(4-trichloromethylphenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis[3,5-di(trifluoromethyl)phenyl]-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis[3,5-di(trichloromethyl)phenyl]-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid,3,3′-bis(4-nitrophenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid, and3,3′-bis(3,5-dinitrophenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diylphosphoricacid.

Example of Application to Asymmetric Reaction

The present invention can be applied to a synthetic reaction using aBroensted acid as a catalyst. That is, by use of a chiral Broensted acidas a catalyst, a chiral compound can be obtained as a reaction product.Examples of the reaction to which the present invention can be appliedinclude an asymmetric Mannich reaction, an asymmetric aza Diels-Alderreaction, an asymmetric allylation reaction, an asymmetrichydrophosphorylation reaction, an asymmetric Strecker reaction, and anasymmetric aminoalkylation reaction of an aromatic compound. However,the reaction examples are not limited to the above as long as a chiralcompound can be obtained using, as a catalyst, a chiralbinaphthol-phosphoric acid derivative of formula (1) or formula (3).

The absolute configuration of a product obtained by the reaction of thepresent invention depends on the absolute configuration of the chiralBroensted acid. That is, when an R-form Broensted acid is used, aproduct having an asymmetric carbon corresponding thereto is given, andwhen an S-form Broensted acid is used, a product having an asymmetriccarbon corresponding thereto is given. When an R-form of formula (1) isused, a product having an asymmetric carbon corresponding thereto isgiven, and when an S-form of formula (1) is used, a product having anasymmetric carbon corresponding thereto is given. With regard to theabsolute configuration of the product, the R-form Broensted acids do notalways give an R-form, and the absolute configuration of the productdepends on the starting material. This also applies to formula (3).

When carrying out an asymmetric synthetic reaction using the catalyst ofthe present invention, for the purpose of removing water from a reactionsystem, various types of zeolite such as A-type zeolite represented bymolecular sieves 3A, 4A, and 5A, molecular sieve 13X, Y-type, or L-typemay be used as necessary.

Asymmetric Mannich Reaction

In an example of the asymmetric Mannich reaction that is carried out byapplying the present invention, an amino compound represented by formula(6) below is obtained from an enol derivative represented by formula (4)below and an imine derivative represented by formula (5) below.

R₅ of formula (4) denotes a hydrogen atom, an optionally branched alkylgroup having 1 to 6 carbons, or an aryl group that may have an alkylgroup having 1 to 6 carbons, R₆ denotes a hydrogen atom or an optionallybranched alkyl group having 1 to 6 carbons, R₇ denotes an optionallybranched alkyl group having 1 to 6 carbons or an optionally branchedalkoxy group having 1 to 6 carbons, and R₈ may each be independent, anddenotes an optionally branched alkyl group having 1 to 6 carbons, aphenyl group, or a phenyl group mono- to tetra-substituted with anoptionally branched alkyl group having 1 to 6 carbons.

R₉ of formula (5) denotes a hydrogen atom, a hydroxyl group, a halogenatom, an optionally branched alkyl group having 1 to 6 carbons, or anoptionally branched alkoxy group having 1 to 6 carbons, and R₁₀ denotesa hydrogen atom, a halogen atom, an optionally branched alkyl grouphaving 1 to 6 carbons, or an optionally branched alkoxy group having 1to 6 carbons.

R₅ to R₇ of formula (6) are the same as those of formula (4), and R₉ andR₁₀ are the same as those of formula (5).

The amount of formula (1) or formula (3) used when the present inventionis applied to the asymmetric Mannich reaction may be in any proportion,but use of too excessive an amount is not economical, and too little anamount might not cause the asymmetric synthesis reaction to progress,which is undesirable. From this, the proportion of the chiral Broenstedacid of formula (1) or formula (3) used when the present invention isapplied to the asymmetric Mannich reaction is equal to or greater than0.01 mol % of the imine derivative represented by formula (5) and isequal to or less than 90 mol %. From this, the proportion of formula (1)or formula (3) used is preferably 0.01 to 90 mol %, more preferably 0.1to 60 mol %, particularly preferably 1 to 50 mol %, and yet moreparticularly preferably 3 to 30 mol %.

When the present invention is applied to other asymmetric syntheses, theproportion of the chiral Broensted acid may be the same proportion asemployed in the asymmetric Mannich reaction.

With regard to an imine that can be used in the asymmetric Mannichreaction in the present invention, any type of imine may be employed,and specific examples are those of formula (5).

More specific examples of the imine compound include a compound offormula (5) in which R₉ is a hydroxyl group and R₁₀ is a hydrogen atom.

With regard to an enol that can be used in the asymmetric Mannichreaction in the present invention, any type of enol can be employed, andspecific examples are those of formula (4).

R₅ of formula (4) is a hydrogen atom, an optionally branched alkyl grouphaving 1 to 6 carbons, or an aryl group that may have an alkyl grouphaving 1 to 6 carbons, is preferably an alkyl group having 1 to 6carbons or an aryl group, and is more preferably a methyl group or anethyl group.

R₆ of formula (4) is a hydrogen atom or an optionally branched alkylgroup having 1 to 6 carbons, preferably an alkyl group having 1 to 6carbons, and more preferably a methyl group or an ethyl group.

R₇ of formula (4) is an optionally branched alkoxy group having 1 to 6carbons or an optionally branched alkyl group having 1 to 6 carbons, ispreferably an optionally branched alkyl group having 1 to 6 carbons, andis more preferably a methyl group, an ethyl group, or a propyl group.

The R₈ groups of formula (4) may be different from each other, and areoptionally branched alkyl groups having 1 to 4 carbons or phenyl groups,preferably optionally branched alkyl groups having 1 to 4 carbons, whichmay be different from each other, and more preferably optionallybranched alkyl groups having 1 to 3 carbons.

Specific examples of the enol compound include one represented byformula (4) in which R₅ and R₆ are methyl groups, R₇ is a methoxy group,and the R₈ groups are methyl groups, one in which R₅ and R₆ are methylgroups, R₇ is a methoxy group, and the R₈ groups are t-butyl and methylgroups, one in which R₅ and R₆ are methyl groups, R₇ is an i-propoxygroup, and the R₈ groups are methyl groups, and one in which R₅ and R₆are hydrogen atoms, R₇ is a methoxy group, and the R₈ groups are methylgroups.

Formula (4) can be obtained from a carboxylic acid ester, a ketone, oran aldehyde and a silyl chloride represented by formula (7) below, etc.(R₈)₃SiCl   (7)

R₈ of formula (7) is the same as R₈ of formula (4).

For example,1-cyclohexenyloxy-[((1-naphthyl)phenyl)methyl]dimethylsilane, which is asilyl enol ether form of cyclohexanone, may be formed by treatingcyclohexanone with lithium diisopropylamide at low temperature (e.g.−78° C.) so as to generate a lithium enolate, and capturing this with[((1-naphthyl)phenyl)methyl]dimethylsilyl chloride. By the same method,a ketone having an active hydrogen such as acetone or benzophenone maybe derivatized to the corresponding silyl enol ether. Furthermore, asilyl ketene acetal form of benzyl acetate may be formed by treatingbenzyl acetate with lithium diisopropylamide at low temperature (e.g.−78° C.) so as to generate a lithium enolate, and capturing this with[((1-naphthyl)phenyl)methyl]dimethylsilyl chloride. By the same method,a carboxylic acid ester having an active hydrogen may be derivatized tothe corresponding silyl ketene acetal.

With regard to ketones that can be employed in order to obtain formula(4) of the present invention, most ketones can be employed, and examplesthereof include acetophenone, (4-methylphenyl)acetophenone,(3-methylphenyl)acetophenone, (2-methylphenyl)acetophenone,(4-ethylphenyl)acetophenone, (3-ethylphenyl)acetophenone,(2-ethylphenyl)acetophenone, (4-i-propylphenyl)acetophenone,(3-i-propylphenyl)acetophenone, (2-i-propylphenyl)acetophenone,1-phenylpropan-1-one, 1-(4-methylphenyl)propan-1-one,1-(3-methylphenyl)propan-1-one, 1-(2-methylphenyl)propan-1-one,1-phenyl-butan-1-one, 1-(4-methylphenyl)-butan-1-one,1-(3-methylphenyl)-butan-1-one, 1-(2-methylphenyl)-butan-1-one,1-phenyl-2-methylpropan-1-one, 1-(4-phenyl)-2-methylpropan-1-one,1-(3-phenyl)-2-methylpropan-1-one, 1-(2-phenyl)-2-methylpropan-1-one,1-phenyl-pentan-1-one, 1-phenyl-hexan-1-one, 1-phenyl-heptan-1-one,1-phenyl-octan-1-one, 1-phenyl-nonan-1-one, 1-phenyl-decan-1-one,1-phenyl-undecan-1-one, 1-phenyl-dodecan-1-one, 1-phenyl-tridecan-1-one,1-phenyl-tetradecan-1-one, 1-phenyl-pentadecan-1-one,1-phenyl-hexadecan-1-one, methyl t-butyl ketone, ethyl glyoxylate, ethylphenyl glyoxylate, methyl phenyl glyoxylate, ethyl i-propyl glyoxylate,ethyl phenylethenyl glyoxylate, and ethyl cyclohexyl glyoxylate.

With regard to aldehydes that can be employed in order to obtain formula(4) of the present invention, most aldehydes can be employed, andexamples thereof include ethyl formate, methoxycarbonyl aldehyde,acetaldehyde, propionaldehyde, butanal, isobutanal, pentanal, acrolein,crotonaldehyde, cyclohexyl aldehyde, benzaldehyde,4-methoxybenzaldehyde, 4-methylbenzaldehyde, 3,5-dimethylbenzaldehyde,4-phenylbenzaldehyde, 4-chlorobenzaldehyde, 4-nitrobenzaldehyde,naphthyl-2-aldehyde, 2-furfural, cinnamaldehyde, 3-phenylpropanal, and2-benzyloxyacetaldehyde and, furthermore, as compounds analogous toaldehydes, a benzylimine, a phenylthioamide, etc. can be cited.

When the method of asymmetric synthesis of the present invention isapplied to the asymmetric Mannich reaction, an imine represented byformula (5) and a ketone or an enol represented by formula (4) are oftenreacted in equimolar amounts, but the ketone or the enol may be used at0.1 to 10 moles per mole of the imine, preferably 1 to 5 moles, and morepreferably 1 to 4 moles.

When the method of asymmetric synthesis of the present invention isapplied to the asymmetric Mannich reaction, most solvents may be used aslong as they are inert to the reaction. Specific examples thereofinclude halogenated solvents such as carbon tetrachloride, chloroform,dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and1,1,2-trichloroethane, ether solvents such as diethyl ether andtetrahydrofuran, and aromatic solvents such as toluene, xylene,ethylbenzene, isopropylbenzene, and mesitylene, and it is preferable touse an aromatic solvent.

When the method of asymmetric synthesis of the present invention isapplied to the asymmetric Mannich reaction, the reaction temperaturedepends on the compound used in the reaction, but it can usually becarried out in the range of −100° C. to 50° C., preferably −80° C. to 0°C., and more preferably −78° C. to −40° C.

When the method of asymmetric synthesis of the present invention isapplied to the asymmetric Mannich reaction, the concentrations offormula (4) and formula (5) used in the reaction are not particularlylimited as long as they can be dissolved in a solvent. Even when theconcentration is too high to be dissolved in a solvent, as long as thereaction is not inhibited the present method of asymmetric synthesis canbe employed. It is usually in the range of 0.1 mass % to 50 mass %relative to the solvent.

When the method of asymmetric synthesis of the present invention isapplied to the asymmetric Mannich reaction, the reaction time depends onthe type of compound and the type of chiral Broensted acid catalyst usedin the reaction, but it may usually be carried out in 1 to 96 hours.

As a posttreatment after the method of asymmetric synthesis of thepresent invention is applied to the asymmetric Mannich reaction, astandard purification method can be used. Specifically, there is amethod in which an appropriate amount of an aqueous solution of sodiumhydrogen carbonate is added to a reaction mixture, it is then extractedwith ethyl acetate, dried over anhydrous sodium sulfate, and filtered,and the filtrate is concentrated to give a product, etc. When purifyingthis product, a standard method such as preparative silica gelthin-layer chromatography, column chromatography, distillation, orrecrystallization can be used.

The asymmetric Mannich reaction to which the present invention isapplied is explained above, but as described above the present inventioncan also be applied to an asymmetric aza Diels-Alder reaction, anasymmetric allylation reaction, an asymmetric hydrophosphorylationreaction, an asymmetric Strecker reaction, an aminoalkylation reactionof an asymmetric aromatic compound, etc.

When the present invention is applied to these asymmetric reactions, theconditions for each reaction may be determined by modifying as necessarythe conditions described for the asymmetric Mannich reaction. That is,the conditions described for the asymmetric Mannich reaction may beemployed while taking into consideration the amount of acid catalyst ineach asymmetric reaction.

Asymmetric aza Diels-Alder Reaction

Examples of the asymmetric aza Diels-Alder reaction to which the presentinvention is applied include one in which formula (9) below is obtainedfrom formula (5) and formula (8) below.

With regard to formula (5) used in the asymmetric aza Diels-Alderreaction, those that can be employed in the asymmetric Mannich reactioncan be used.

R₈ of formula (8) may be the same as R₈ of formula (4), and R₁₁ denotesan optionally branched alkyl group having 1 to 6 carbons. It ispreferably a methyl group or an ethyl group.

R₉ and R₁₀ of formula (9) are the same as those of formula (5).

Asymmetric Allylation Reaction

Examples of the asymmetric allylation reaction to which the presentinvention is applied include one in which formula (12) below is obtainedfrom formula (10) below and formula (11) below.R₁₂—CH═N—R₁₃   (10)

R₁₂ of formula (10) denotes an optionally branched alkyl group having 1to 6 carbons or an aryl group having a substituent, and R₁₃ denotes anaryl group that may have a substituent such as a hydroxyl group.CH₂═CH—CH₂—B1   (11)

B1 of formula (11) denotes a trialkylstannyl group or a trialkylsilylgroup, and this alkyl group is an optionally branched one having 1 to 6carbons.

R₁₂ and R₁₃ of formula (12) are the same as those of formula (10).

R₁₂ of formula (10) denotes an optionally branched alkyl group having 1to 6 carbons or an aryl group having a substituent, and preferredexamples thereof include a methyl group, an ethyl group, and a phenylgroup. R₁₃ denotes an aryl group that may have a substituent such as ahydroxyl group; preferred examples thereof include a phenyl group and aphenyl group having a hydroxyl group, and it is particularly preferablya 2-hydroxyphenyl group.

B1 of formula (11) denotes a trialkylstannyl group or a trialkylsilylgroup; this alkyl group is an optionally branched one having 1 to 6carbons, and is preferably a methyl group or an ethyl group.

R₁₂ and R₁₃ of formula (12) are the same as those of formula (10).

Asymmetric Hydrophosphorylation Reaction

Examples of the asymmetric hydrophosphorylation reaction to which thepresent invention is applied include one in which formula (14) isobtained from formula (10) and formula (13) below.(R₁₄O)₂POH   (13)

R₁₄ of formula (13) denotes an optionally branched alkyl group having 1to 6 carbons.

R₁₂ and R₁₃ of formula (14) are the same as those of formula (10), andR₁₄ is the same as that of formula (13).

R₁₄ of formula (13) denotes an optionally branched alkyl group having 1to 6 carbons, and is preferably a methyl group or an ethyl group.

R₁₂ and R₁₃ of formula (14) are the same as those of formula (10), andR₁₄ is the same as that of formula (13).

Asymmetric Strecker Reaction

Examples of the asymmetric Strecker reaction to which the presentinvention is applied include one in which formula (16) is obtained fromformula (10) and formula (15) below.B2-CN   (15)

B2 of formula (15) denotes a hydrogen atom, a trialkylstannyl group, ora trialkylsilyl group, and this alkyl group is an optionally branchedone having 1 to 6 carbons.

R₁₂ and R₁₃ of formula (16) are the same as those of formula (10).

B2 of formula (15) denotes a hydrogen atom, a trialkylstannyl group, ora trialkylsilyl group; this alkyl group is an optionally branched onehaving 1 to 6 carbons, and is preferably a methyl group or an ethylgroup.

R₁₂ and R₁₃ of formula (16) are the same as those of formula (10).

Asymmetric Aminoalkylation Reaction of Aromatic Compound

Examples of the asymmetric aminoalkylation reaction of an aromaticcompound to which the present invention is applied include one in whichformula (18) is obtained from formula (10) and formula (17) below.

With regard to R₁₅ of formula (17), a plurality thereof may be bonded,and when a plurality thereof are bonded, they may be different from eachother. R₁₅ denotes a hydroxyl group, a halogen atom, an optionallybranched alkyl group having 1 to 6 carbons, or an optionally branchedalkoxy group having 1 to 6 carbons.

R₁₂ and R₁₃ of formula (18) are the same as those of formula (10), andR₁₅ is the same as that of formula (17).

With regard to R₁₅ of formula (17), a plurality thereof may be bonded,and when a plurality thereof are bonded, they may be different from eachother. R₁₅ denotes a hydroxyl group, a halogen atom, an optionallybranched alkyl group having 1 to 6 carbons, or an optionally branchedalkoxy group having 1 to 6 carbons. The optionally branched alkyl grouphaving 1 to 6 carbons is preferably a methyl group, an ethyl group, or apropyl group, and the optionally branched alkoxy group having 1 to 6carbons is preferably a methoxy group or an ethoxy group.

R₁₂ and R₁₃ of formula (18) are the same as those of formula (10), andR₁₅ is the same as that of formula (17).

The present invention may be applied to a synthetic reaction using aBroensted acid as a catalyst, thus giving a chiral compound. Here, sinceno metal salt or metal complex is used, the burden on the environment issmall. Furthermore, with regard to the conditions of the asymmetricsynthesis to which the present invention is applied, the conditions ofthe synthetic reaction using a Broensted acid as a catalyst can be usedwith hardly any modification.

The chiral compounds obtained by application of the present inventionare useful as compounds used in perfumes, pharmaceuticals,agrochemicals, etc. and synthetic intermediates therefor.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (1), in formula (1), R₁, R₂, R₃,and R₄ may be independent of each other, and denote a hydrogen atom (R₁,R₂, R₃, and R₄ are not hydrogen atoms simultaneously); an aryl group; anaryl group mono- or di-substituted with an aryl group; an aryl groupmono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁, —COOA₂, an optionally branched alkyl grouphaving 1 to 10 carbons, an optionally branched alkenyl group having 1 to10 carbons, and an optionally branched alkoxy group having 1 to 20carbons; an aryl group mono- or di-substituted with an aryl group thatmay be mono- to tetra-substituted with at least one type selected fromthe group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁, —COOA₂, and an optionallybranched alkyl group having 1 to 20 carbons; a cycloalkyl group having 3to 8 carbons; or formula (2). A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons, and A₂ denotes an optionally branched alkylgroup having 1 to 6 carbons. Furthermore, it is not desirable that ahydrogen atom is bonded as R₁ or R₂.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (3), in formula (3), R₁ and R₂ maybe independent of each other, and denote a hydrogen atom (R₁ and R₂ arenot hydrogen atoms simultaneously); an aryl group; an aryl group mono-or di-substituted with an aryl group; an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, an optionally branched alkyl group having 1to 10 carbons, an optionally branched alkenyl group having 1 to 10carbons, and an optionally branched alkoxy group having 1 to 20 carbons;an aryl group mono- or di-substituted with an aryl group that may bemono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁, —COOA₂, and an optionally branched alkylgroup having 1 to 20 carbons; a cycloalkyl group having 3 to 8 carbons;or formula (2). A₁ denotes an optionally branched alkyl group having 1to 6 carbons, and A₂ denotes an optionally branched alkyl group having 1to 6 carbons. Furthermore, it is not desirable that a hydrogen atom isbonded as R₁ or R₂.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (1), in formula (1), R₃ and R₄ maybe independent of each other, and denote a hydrogen atom, a halogenatom, a nitro group, a monohalogenomethyl group, a dihalogenomethylgroup, a trihalogenomethyl group, a nitrile group, a formyl group,—COA₁, —COOA₂, an optionally branched alkyl group having 1 to 20carbons, an optionally branched alkenyl group having 3 to 20 carbons, anoptionally branched alkoxy group having 1 to 20 carbons, or an arylgroup, and R₁ and R₂ may be independent of each other, and denote anaryl group; an aryl group mono- or di-substituted with an aryl group; anaryl group mono- to tetra-substituted with at least one type selectedfrom the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁, —COOA₂, an optionallybranched alkyl group having 1 to 10 carbons, an optionally branchedalkenyl group having 1 to 10 carbons, and an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group mono- or di-substituted withan aryl group that may be mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁, —COOA₂,and an optionally branched alkyl group having 1 to 20 carbons; acycloalkyl group having 3 to 8 carbons; or formula (2). A₁ denotes anoptionally branched alkyl group having 1 to 6 carbons, and A₂ denotes anoptionally branched alkyl group having 1 to 6 carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (3), R₁ and R₂ may be independentof each other, and denote an aryl group; an aryl group mono- ordi-substituted with an aryl group; an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, an optionally branched alkyl group having 1to 10 carbons, an optionally branched alkenyl group having 1 to 10carbons, and an optionally branched alkoxy group having 1 to 20 carbons;an aryl group mono- or di-substituted with an aryl group that may bemono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁, —COOA₂, and an optionally branched alkylgroup having 1 to 20 carbons; a cycloalkyl group having 3 to 8 carbons;or formula (2). A₁ denotes an optionally branched alkyl group having 1to 6 carbons, and A₂ denotes an optionally branched alkyl group having 1to 6 carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (1), in formula (1), R₃ and R₄ maybe independent of each other, and denote a hydrogen atom, a halogenatom, a nitro group, a monohalogenomethyl group, a dihalogenomethylgroup, a trihalogenomethyl group, a nitrile group, a formyl group,—COA₁, —COOA₂, or an optionally branched alkoxy group having 1 to 20carbons, and R₁ and R₂ may be independent of each other, and denote anaryl group mono- or di-substituted with an aryl group; an aryl groupmono- to tetra-substituted with at least one type selected from thegroup consisting of a nitro group, a halogen atom, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, a nitrilegroup, a formyl group, —COA₁, —COOA₂, and an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group mono- or di-substituted withan aryl group that may be mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁, —COOA₂,and an optionally branched alkyl group having 1 to 20 carbons; orformula (2). A₁ denotes an optionally branched alkyl group having 1 to 6carbons, and A₂ denotes an optionally branched alkyl group having 1 to 6carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (3), R₁ and R₂ may be independentof each other, and denote an aryl group mono- or di-substituted with anaryl group; an aryl group mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁, —COOA₂,and an optionally branched alkoxy group having 1 to 20 carbons; an arylgroup mono- or di-substituted with an aryl group that may be mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, and an optionally branched alkyl grouphaving 1 to 20 carbons; or formula (2). A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons, and A₂ denotes an optionallybranched alkyl group having 1 to 6 carbons.

In a method of asymmetric synthesis using as a catalyst a chiralBroensted acid represented by formula (1), in formula (1), R₃ and R₄ maybe independent of each other, and denote a hydrogen atom, a halogenatom, a nitro group, an optionally branched alkyl group having 1 to 20carbons, an optionally branched alkoxy group having 1 to 20 carbons, oran aryl group, and R₁ and R₂ may be independent of each other, anddenote an aryl group; an aryl group mono- or di-substituted with an arylgroup; an aryl group mono- to tetra-substituted with at least one typeselected from the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁, —COOA₂, an optionallybranched alkyl group having 1 to 10 carbons, an optionally branchedalkenyl group having 1 to 10 carbons, and an optionally branched alkoxygroup having 1 to 20 carbons; or formula (2). A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons, and A₂ denotes an optionallybranched alkyl group having 1 to 6 carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (3), R₁ and R₂ may be independentof each other, and denote an aryl group; an aryl group mono- ordi-substituted with an aryl group; an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, an optionally branched alkyl group having 1to 10 carbons, an optionally branched alkenyl group having 1 to 10carbons, and an optionally branched alkoxy group having 1 to 20 carbons;or formula (2). A₁ denotes an optionally branched alkyl group having 1to 6 carbons, and A₂ denotes an optionally branched alkyl group having 1to 6 carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (1), in formula (1), R₃ and R₄ maybe independent of each other, and denote a hydrogen atom or a halogenatom, and R₁ and R₂ may be independent of each other, and denote an arylgroup; an aryl group mono- or di-substituted with an aryl group; or anaryl group mono- to tetra-substituted with at least one type selectedfrom the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁, —COOA₂, and an optionallybranched alkoxy group having 1 to 20 carbons. A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons, and A₂ denotes an optionallybranched alkyl group having 1 to 6 carbons.

In a method of asymmetric synthesis using, as a catalyst, a chiralBroensted acid represented by formula (3), in formula (1) R₁ and R₂ maybe independent of each other, and denote an aryl group; an aryl groupmono- or di-substituted with an aryl group; or an aryl group mono- totetra-substituted with at least one type selected from the groupconsisting of a nitro group, a halogen atom, a monohalogenomethyl group,a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, aformyl group, —COA₁, —COOA₂, and an optionally branched alkoxy grouphaving 1 to 20 carbons. A₁ denotes an optionally branched alkyl grouphaving 1 to 6 carbons, and A₂ denotes an optionally branched alkyl grouphaving 1 to 6 carbons.

A method of asymmetric synthesis using a chiral Broensted acid as acatalyst in an aromatic solvent.

A method of asymmetric synthesis using formula (1) or formula (3) as acatalyst in an aromatic solvent.

EXAMPLES

Hereinafter, the present invention will be described specifically bymeans of Examples, but the invention is not intended to be limited tothese Examples. M represents molar concentration (mol/L). As forsynthetic operations, the inside of the reaction system was substitutedwith nitrogen gas, and reagents and solvents were dehydrated before use.

Synthetic Example 1 Synthesis of (R)-2,2′-dimethoxy-1,1′-binaphthyl(GA06)

(R)-1,1′-binaphthyl-2,2′-diol (referred to as (R)-BINOL), methyl iodide,and potassium carbonate were refluxed in acetone for 30 hours to giveGA06.

Synthetic Example 2 Synthesis of(R)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (GA12)

Diethyl ether (200 mL) and N,N,N′,N′-tetramethylethylenediamine (TMEDA;26.2 mmol) were put in a three-necked round bottom flask and stirred.n-Butyllithium (n-BuLi; 48.9 mmol) was added dropwise over 20 minutes ormore at room temperature. After that, GA06 (19.1 mmol) obtained inSynthetic example 1 was added, which was stirred overnight. The reactionmixture was cooled to −78° C. A solution prepared by dissolving iodine(71.2 mmol) in tetrahydrofuran (24 mL) was added dropwise, and thereaction mixture was stirred for 1 hour. Then, the mixture was warmed toroom temperature and stirred for additional 12 hours. The reactionmixture was cooled to 0° C., and then the reaction was quenched by theaddition of water and stirring for 2 hours. The solution was extractedwith diethyl ether three times. The combined extracts was washed with anaqueous sodium thiosulfate solution and brine, and dried over anhydroussodium sulfate. After the drying, the extracts was filtered, thefiltrate was concentrated and then separated and purified by means ofcolumn chromatography to give GA12 (10.6 mmol, yield: 55%).

Rf=0.3(Hexane:CH₂Cl₂=6:1).

¹H-NMR(400 MHz,CDCl₃) δ=8.53(s,2H), 7.80(d,2H,J=7.7 Hz), 7.41(m,2H),7.27(m,2H), 7.07(d,2H,J=8.6 Hz), 3.42(s,6H).

Synthetic Example 3 Synthesis of(R)-3,3′-diphenyl-2,2′-dimethoxy-1,1′-binaphthyl (GA03)

GA12 (7.1 mmol) obtained in Synthetic example 2, Nickel (II)acetylacetonate (Ni(ACAC)₂, 0.73 mmol) and benzene (40 mL) were put in athree-necked round bottom flask. Phenyl MgBr prepared separately wasadded dropwise over 10 minutes or more at room temperature, and thereaction mixture was stirred for additional 30 minutes. Then, themixture was heated and refluxed for 12 hours. The reaction mixture wascooled to 0° C., and then the reaction was quenched by the addition of 1M hydrochloric acid and stirring for 1 hour. The reaction mixture wasextracted with diethyl ether three times. The combined extracts waswashed with brine and dried over anhydrous sodium sulfate. After thedrying, the extract was filtered, the filtrate was concentrated and thenseparated and purified by means of column chromatography to give GA03.

Synthetic Example 4 Synthesis of(R)-3,3′-diphenyl-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (GA04)

GA03 (1.91 mmol) obtained in Synthetic example 3 and pyridine (7.8 mL)were put in a two-necked round bottom flask. To the solution, phosphorylchloride (2.69 mmol) was added dropwise over 7 minutes at roomtemperature. The reaction mixture was stirred for additional 2 hours.Then, the reaction mixture was heated and refluxed for 1 hour. Thereaction mixture was cooled to room temperature, and distillated water(1.6 mL) was added dropwise. Then, the mixture was heated and refluxedfor 1.5 hours and cooled to room temperature. Pyridine was distilledaway under a reduced pressure from the mixture. Subsequently, 6 Mhydrochloric acid (15 mL) was added dropwise to the mixture and heatedand refluxed for additional 2 hours. The reaction mixture was cooled to0° C. and filtered. The filtrate was washed with water and dried. Thecrude product was recrystallized in methanol to give GA04.

Synthetic Example 5 Synthesis of(R)-3,3′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl (GA07)

GA06 (12.6 mmol) obtained in Synthetic example 1 and 200 mL of diethylether were put in a three-necked round bottom flask, n-BuLi (37.4 mmol)and TMEDA (30 mmol) were added at room temperature, and the reactionmixture was stirred for 3 hours. The reaction mixture was cooled to −78°C. A solution prepared by dissolving bromine (177 mmol) in 50 mL ofdiethyl ether was added dropwise. The mixture was stirred for 4 hours.Then, an aqueous sodium thiosulfate solution was added to quench thereaction. The mixture was extracted with diethyl ether three times. Theextract was washed with a saturated aqueous sodium chloride solutionfollowed by dehydration over anhydrous sodium sulfate. After thedehydration, the extract was filtered. After distilling the solvent awayunder a reduced pressure, the filtrate was purified by means of columnchromatography (Hexane:Ethyl acetate (AcOEt)=5:1) to give GA07.

Synthetic Example 6 Synthesis of (R)-3,3′-dibromo-1,1′-binaphthol (GA08)

GA07 (5.77 mmol) obtained in Synthetic example 5 and dichloromethane (55mL) were put in a three-necked round bottom flask and cooled to 0° C. Tothe solution, A solution prepared by dissolving 7.9 g of Borontribromide (BBr₃, 5.47 mmol) in 20 mL of dichloromethane was addeddropwise. After the adding dropwise, the mixture was warmed to roomtemperature and stirred for additional 5 hours. Then, it was cooled to0° C., and the reaction was quenched by the addition of water. Thesolution was extracted with dichloromethane three times. The combinedextracts was washed with brine and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. The filtrate wasconcentrated to give solid material, and the obtained solid wasseparated and purified by means of column chromatography to give GA08(5.39 mmol, yield: 93%).

Rf=0.2(Hexane:CH₂Cl₂=2:1).

¹H-NMR(400 MHz,CDCl₃) δ=8.24(s,2H), 7.80(d,2H,J=8.1 Hz),7.37(dd,2H,J=8.2,8.1 Hz), 7.29(dd,2H,J=8.2,8.4 Hz), 7.09(d,2H,J=8.4 Hz),5.54(s,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=148.01, 132.75, 129.72, 127.56, 127.38, 124.84,124.62, 114.62, 112.25.

Synthetic Example 7 Synthesis of (R)-3,3′-dibromo-2,2′-bis(triphenylsiloxy)-1,1′-binaphthyl (GA09)

GA08 (1.89 mmol) obtained in Synthetic example 6 and DMF were put in atwo-necked round bottom flask. To the flask, Imidazole (5.29 mmol) andTriphenylsilyl chloride (5.79 mmol) were added, and the reaction mixturewas stirred at room temperature for 5 hours. After 5 hours,disappearance of GA08 was checked by means of TLC. Then, the solutionwas cooled to 0° C., and the reaction was quenched by the addition of asaturated aqueous sodium hydrogen carbonate solution dropwise. Thereaction mixture was extracted with ethyl acetate three times. Thecombined extracts was washed with 1 M hydrochloric acid and brine, anddried over anhydrous sodium sulfate. After the drying, the extract wasfiltered, and the filtrate was concentrated. The obtained solid wasseparated and purified by means of column chromatography to give GA09(1.87 mmol, yield: 99%).

Rf=0.4(Hexane:CH₂Cl₂=2:1).

¹H-NMR(400 MHz,CDCl₃) δ=7.65(s,2H), 7.46(d,2H,J=7.5 Hz),7.41-7.35(m,4H), 7.28-7.24(m,20H), 7.18-7.02(m,20H), 6.82(d,2H,J=8.6Hz).

Synthetic Example 8 Synthesis of(R)-3,3′-bis(triphenylsilyl)-1,1′-binaphthol (GA10)

GA09 (2.69 mmol) obtained in Synthetic example 7 and tetrahydrofuran (40mL) were put in a three-necked round bottom flask and cooled to 0° C. Tothe solution, t-Butyllithium (t-BuLi; 5.47 mmol) was added dropwise over10 minutes or more. After the adding dropwise, the reaction mixture waswarmed to room temperature and stirred for additional 1.5 hours. Then,the mixture was cooled to 0° C., a saturated aqueous ammonium chloridesolution was added to quench the reaction. The reaction mixture wasextracted with dichloromethane three times. The combined extracts waswashed with brine and dried over anhydrous sodium sulfate. After thedrying, the extract was filtered, and the filtrate was concentrated. Theobtained solid was separated and purified by means of columnchromatography to give GA10 (2.69 mmol, quant.).

Rf=0.4(Hexane:CH₂Cl₂=2:1).

¹H-NMR(400 MHz,CDCl₃) δ=7.91(s,2H), 7.72-7.23(m,38H), 5.29(s,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=156.51, 142.08, 136.40, 136.31, 135.19, 134.77,134.28, 129.78, 129.51, 129.23, 129.07, 128.18, 127.82, 127.70, 123.91,123.85, 123.68, 110.66, 96.14.

Synthetic Example 9 Synthesis of(R)-3,3′-bis(triphenylsilyl)-1,1′-binaphthyl-2,2′-diylhydrogen-phosphate (GA11)

GA10 (0.94 mmol) obtained in Synthetic example 8 and tetrahydrofuran (8mL) were put in a two-necked round bottom flask and cooled to −20° C. Tothe flask, n-BuLi (2.0 mmol) was added dropwise over 5 minutes. Thereaction mixture was warmed to room temperature and stirred foradditional 2 hours. To the reaction mixture, a solution prepared bydiluting phosphoryl chloride (1.1 mmol) in tetrahydrofuran (3.5 mL) wasadded dropwise over 15 minutes and the mixture was stirred at roomtemperature for additional 1 hour. Then, distillated water (0.4 mL) andtriethylamine were added, and the mixture was heated and refluxed for 5hours. The reaction mixture was cooled to room temperature. The solventwas distilled away under a reduced pressure. Then the 6 M hydrochloricacid (12 mL) was added. The mixture was heated and refluxed for 5 hours.The reaction mixture was cooled to 0° C. and filtered. The filtrate waswashed with water and dried. The obtained solid was separated from thestarting materials with Hexane:Toluene=1:1 by means of columnchromatography. Then the solid was eluted with toluene to give GA11(0.54 mmol, yield: 57%).

¹H-NMR(400 MHz,CDCl₃) δ=8.15(d,2H,J=9.0 Hz), 7.82(d,2H,J=8.2 Hz),7.66-7.60(m,12H), 7.47-7.14(m,24H).

Synthetic Example 10 Synthesis of(R)-3,3′-dimesityl-2,2′-dimethoxy-1,1′-binaphthyl (GA13)

GA12 (7.1 mmol) obtained in Synthetic example 2, Ni(ACAC)₂ (0.73 mmol)and benzene (40 mL) were put in a three-necked round bottom flask.Mesityl MgBr prepared separately was added dropwise to the solution over10 minutes or more at room temperature and the reaction mixture wasstirred for additional 30 minutes. After that, the mixture was heatedand refluxed for 12 hours. The reaction mixture was cooled to 0° C., andthe reaction was quenched by the addition of 1 M hydrochloric acid andstirring for 1 hour. The reaction mixture was extracted with diethylether three times. The combined extracts was washed with brine and driedover anhydrous sodium sulfate. After the drying, the extract wasfiltered. The filtrate was concentrated, and separated and purified bymeans of column chromatography to give GA13 (5.03 mmol, yield: 71%).

Rf=0.3(Hexane:CH₂Cl₂=6:1).

¹H-NMR(400 MHz,CDCl₃) δ=7.85(d,2H,J=8.1 Hz), 7.69(s,2H),7.41-7.37(m,2H), 7.26(s,4H), 6.97(s,4H), 3.10(s,6H), 2.35(s,6H),2.18(s,6H), 2.13(s,6H).

Synthetic Example 11 Synthesis of (R)-3,3′-dimesityl-1,1′-binaphthol(GA14)

GA13 obtained in Synthetic example 10 was subjected to the samedeprotection procedure as that in Synthetic example 6 to give GA14(yield: 95%)

Rf=0.3(Hexane:CH₂Cl₂=2:1).

¹H-NMR(400 MHz,CDCl₃) δ=7.84(d,2H,J=8.1 Hz), 7.72(s,2H),7.36-7.23(m,6H), 6.98(s,4H), 5.00(s,4H), 2.31(s,6H), 2.13(s,6H),2.06(s,6H).

¹³C-NMR(100 MHz,CDCl₃) δ=149.97, 137.71, 137.10, 137.04, 133.39, 132.88,130.62, 129.43, 129.40, 128.49, 128.41, 128.21, 126.78, 124.51, 123.82,112.94, 21.11, 20.50, 20.41.

Synthetic Example 12 Synthesis of(R)-3,3′-dimesityl-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (GA15)

GA14 (1.91 mmol) obtained in Synthetic example 11 and pyridine (7.8 mL)were put in a two-necked round bottom flask. To the flask, phosphorylchloride (2.69 mmol) was added dropwise over 7 minutes at roomtemperature and the reaction mixture was stirred for additional 2 hours.After that, the mixture was heated and refluxed for 1 hour. The reactionmixture was cooled to room temperature. Distillated water (1.6 mL) wasadded dropwise and the mixture was heated and refluxed for 1.5 hours.After that, the mixture was cooled to room temperature, pyridine wasdistilled away under a reduce pressure. Then 6 M hydrochloric acid (15mL) was added dropwise, and the mixture was heated and refluxed foradditional 2 hours. The reaction mixture was cooled to 0° C. andfiltered. The filtrate was washed with water and dried. The extract wasrecrystallized in methanol to give GA15 (1.30 mmol, yield: 68%).

¹H-NMR(400 MHz,CDCl₃) δ=7.89(d,2H,J=8.1 Hz), 7.73(s,2H),7.48-7.44(t,2H,J=7.3 Hz), 7.36(d,2H,J=8.6 Hz), 7.29(d,2H,J=7.5 Hz),6.76(s,2H), 6.68(s,2H), 2.13(s,6H), 2.00(s,6H), 1.96(s,6H).

Synthetic Example 13 Synthesis of(R)-3,3′-bis(dihydroxyborane)-2,2′-dimethoxy-1,1′-binaphthyl (GA16)

Diethyl ether (300 mL) and TMEDA (55.1 mmol) were put in a three-neckedround bottom flask, to which was added dropwise n-BuLi (56.2 mmol) over5 minutes or more at room temperature. Further GA06 (19.1 mmol) obtainedin Synthetic example 1 was added thereto and the mixture was stirred for3 hours. The reaction mixture was cooled to −78° C. (EtO)₃B (117.5 mmol)was added dropwise over 10 minutes or more. The reaction mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas cooled to 0° C., the reaction was quenched by the addition of 1 Mhydrochloric acid and stirring for 2 hours. The reaction mixture wasextracted with diethyl ether three times. The combined extracts waswashed with 1 M hydrochloric acid twice and with brine once, and driedover anhydrous sodium sulfate. After the drying, the extract wasfiltered. The filtrate was concentrated to give a solid, which wasrecrystallized twice in toluene to give GA16 (12.0 mmol, yield: 63%).

¹H-NMR(400 MHz,CDCl₃) δ=8.62(s,2H), 7.99(d,2H,J=8.1 Hz), 7.44(t,2H,J=7.6Hz), 7.32(t,2H,J=7.6 Hz), 7.16(d,2H,J=8.2 Hz), 6.12(brs,4H), 3.31(s,6H).

Synthetic Example 14 Synthesis of(R)-3,3′-Bis(4-biphenyl)-1,1′-binaphthol (GA18)

GA16 (4.98 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, 4-bromobiphenyl (15.0 mmol)was added, and the reaction mixture was heated and refluxed for 22hours. The reaction mixture was cooled to room temperature, form whichdioxane was distilled away under a reduced pressure. 1M hydrochloricacid was added, and then the mixture extracted with dichloromethanethree times. The combined extracts was washed with 1M hydrochloric acidtwice and with brine once, and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. The filtrate wasconcentrated to give a solid, and the obtained solid was deprotected inthe same procedure as that in Synthetic example 6. 4-Bromobiphenyl wasfirstly separated from the obtained solid with Hexane:CH₂Cl₂=4:1 bymeans of column chromatography, and then GA18 (4.30 mmol, yield: 86%)was separated and purified with Hexane:CH₂Cl₂=1:1.

Rf=0.5.

¹H-NMR(400 MHz,CDCl₃) δ=8.08(s,2H), 7.93(d,2H,J=7.9 Hz),7.84-7.81(m,4H), 7.72-7.70(m,4H), 7.67-7.65(m,4H), 7.47-7.22(m,4H),5.40(s,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=150.23, 140.74, 140.58, 136.41, 132.92, 131.39,130.24, 130.00, 129.50, 128.80, 128.48, 127.42, 127.40, 127.18, 127.12,124.40, 124.25, 112.30.

Synthetic Example 15 Synthesis of(R)-3,3′-bis(4-biphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate(GA19)

GA18 obtained in Synthetic example 14 was subjected to the sameprocedure as that in Synthetic example 12 to give a solid content. Thesolid content was recrystallized in n-hexane and dichloromethane toseparate and purify GA19 (1.59 mmol, yield: 84%).

¹H-NMR(400 MHz,CDCl₃) δ=8.20(brs,2H), 8.07(s,2H), 7.97(d,2H,J=8.1 Hz),7.88(d,2H,J=8.1 Hz), 7.62-7.29(m,20H).

¹³C-NMR(100 MHz,CDCl₃) δ=141.32, 140.41, 139.67, 136.88, 133.70, 132.23,131.26, 130.83, 130.45, 128.73, 128.31, 127.28, 126.99, 126.81, 126.52,126.26, 126.05, 125.48, 123.14.

Synthetic Example 16 Synthesis of(R)-3,3′-bis(2-naphthyl)-1,1′-binaphthol (GA28)

GA16 (4.98 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, 2-bromonaphthalene (15.0mmol) was added, and the reaction mixture was heated and refluxed for 22hours. The reaction mixture was cooled to room temperature, dioxane wasdistilled away under a reduced pressure. After addition of 1 Mhydrochloric acid, the mixture was extracted with dichloromethane threetimes. The combined extracts was washed with 1 M hydrochloric acid twiceand with brine once, and dried over anhydrous sodium sulfate. After thedrying, the extract was filtered. The filtrate was concentrated to givea solid, the obtained solid was deprotected in the same procedure asthat in Synthetic example 6. 2-Bromonaphthalene was firstly separatedfrom the obtained solid with Hexane:CH₂Cl₂=4:1 by means of columnchromatography, and then GA28 (3.26 mmol., yield: 82%) was separated andpurified with Hexane:CH₂Cl₂=2:1.

Rf=0.4.

¹H-NMR(400 MHz,CDCl₃) δ=8.21(s,2H), 8.13(s,2H), 7.96-7.86(m,10H),7.53-7.47(m,4H), 7.43-7.28(m,6H), 5.46(brs,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=150.30, 135.00, 133.45, 133.03, 132.76, 131.69,130.63, 129.53, 128.50, 128.20, 127.92, 127.67, 127.43, 126.27, 126.23,124.40, 124.32, 112.48.

Synthetic Example 17 Synthesis of(R)-3,3′-bis(2-naphthyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate(GA29)

GA28 obtained in Synthetic example 16 was subjected to the sameprocedure as that in Synthetic example 12 to give a solid content. Theobtained solid content was recrystallized in ethanol to give GA29 (1.75mmol, yield: 72%).

¹H-NMR(400 MHz,CDCl₃) δ=8.03(s,4H), 7.97(d,2H,J=8.4 Hz), 7.69(d,2H,J=8.1Hz), 7.59(d,2H,J=7.3 Hz), 7.47(d,8H,J=8.1 Hz), 7.33-7.19(m,6H),6.53(brs,1H).

¹³C-NMR(100 MHz,CDCl₃) δ=146.09, 142.52, 141.30, 140.53, 135.51, 134.26,133.01, 132.40, 132.25, 131.31, 131.04, 128.77, 128.39, 128.29, 127.35,127.14, 126.19, 125.56, 125.39, 124.91, 123.27.

Synthetic Example 18 Synthesis of p-bromo-iodobenzene (GA31)

p-Dibromobenzene and diethyl ether (135 mL) were put in a three-neckedround bottom flask and cooled to −78° C., t-BuLi (89.60 mmol) was addeddropwise and the reaction mixture was stirred for 30 minutes. To thereaction mixture, iodine (44.90 mmol) dissolved in tetrahydrofuran (15mL) was added over 15 minutes. The mixture was stirred for 30 minutes,warmed to room temperature, and then stirred for additional 4 hours. Thereaction mixture was cooled to 0° C. The reaction was quenched by theaddition of a saturated aqueous sodium thiosulfate solution. Thereaction mixture was extracted with ethyl acetate three times. Thecombined extracts was washed with brine and dried over anhydrous sodiumsulfate. After the drying, the extract was filtered. The filtrate wasconcentrated to give a solid, which was recrystallized in ethanol togive GA31 (36.70 mmol, yield: 82%).

¹H-NMR(400 MHz,CDCl₃) δ=7.56-7.53(m,2H), 7.26-7.21(m,2H).

Synthetic Example 19 Synthesis of 2,4,6-trimethylboronic acid (GA33)

Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in athree-necked round bottom flask and stirred. To the solution,bromomesitylene (13.07 mmol) was added, and the reaction mixture washeated. After that, bromomesitylene (32.02 mmol) dissolved intetrahydrofuran (30 mL) was added dropwise to the solution. The reactionmixture was heated and refluxed for 4.5 hours. Then, the mixture wascooled to −78° C. (EtO)₃B (111.66 mmol) was added dropwise over 15minutes. After that, the mixture was warmed to room temperature andstirred for additional 5 hours. Then the mixture was cooled to 0° C. Thereaction was quenched by the addition of 1 M hydrochloric acid andstirring for additional 2 hours. The reaction mixture was extracted withdiethyl ether three times. The combined extracts was washed with brineand dried over anhydrous sodium sulfate. After the drying, the extractwas filtered. The filtrate was concentrated to give a solid, which wasrecrystallized in benzene to give GA33 (26.10 mmol, yield: 58%).

¹H-NMR(400 MHz,CDCl₃) δ=6.82(s,2H), 4.73(brs,2H), 2.33(s,6H),2.26(s,3H).

¹³C-NMR(100 MHz,CDCl₃) δ=139.64, 138.66, 127.99, 127.26, 22.89, 22.03,21.12.

Synthetic Example 20 Synthesis of 4-Bromo-2′,4′,6′-trimethylbiphenyl(GA35)

GA33 (4.98 mmol) obtained in Synthetic example 19, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, GA31 (15.0 mmol) obtained inSynthetic example 18 was added, and the reaction mixture was heated andrefluxed for 22 hours. The reaction mixture was cooled to roomtemperature. Dioxane was distilled away under a reduced pressure. Afteraddition of 1 M hydrochloric acid, the mixture was extracted withdichloromethane three times. The combined extracts was washed with 1 Mhydrochloric acid twice and with brine once, and dried over anhydroussodium sulfate. After the drying, the extract was filtered. By means ofcolumn chromatography, the obtained solid was firstly separated withHexane:CH₂Cl₂=2:1, and then separated and purified withHexane:CH₂Cl₂=1:1 to give GA35 (11.50 mmol, yield: 86%).

Rf=0.6.

¹H-NMR(400 MHz,CDCl₃) δ=7.52(d,2H,J=8.2 Hz), 7.00(d,2H,J=8.2 Hz),6.92(s,2H), 2.31(s,3H), 1.98(s,6H).

¹³C-NMR(100 MHz,CDCl₃) δ=139.95, 137.66, 136.89, 135.74, 131.56, 131.07,128.13, 120.60, 20.99, 20.68.

Synthetic Example 21 Synthesis of(R)-3,3′-bis[4-(2′,4′,6′-trimethylbipheny1)]-1,1′-binaphthol (GA37)

GA16 (4.98 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, GA35 (15.0 mmol) obtained inSynthetic example 20 was added, and the reaction mixture was heated andrefluxed for 22 hours. The reaction mixture was cooled to roomtemperature. Dioxane was distilled away under a reduced pressure. Afterthe addition of 1 M hydrochloric acid, the mixture was extracted withdichloromethane three times. The combined extracts was washed with 1 Mhydrochloric acid twice and with brine once, and dried over anhydroussodium sulfate. After the drying, the extract was filtered. The filtratewas concentrated to give a solid, which was deprotected in the sameprocedure as that in Synthetic example 6. The obtained solid wasseparated and purified by means of column chromatography to give GA37(2.85 mmol, yield: 78%).

Rf=0.5(Hexane).

¹H-NMR(400 MHz,CDCl₃) δ=8.12(s,2H), 7.95(d,2H,J=8.2 Hz), 7.81(d,2H,J=8.4 Hz), 7.42-7.39(m,2H), 7.36-7.32(m,2H), 7.28-7.24(m,6H),6.97(s,4H), 5.45(s,2H), 2.34(s,6H), 2.07(s,12H).

¹³C-NMR(100 MHz,CDCl₃) δ=150.18, 140.59, 138.61, 136.67, 136.03, 135.56,132.95, 131.37, 130.46, 129.54, 129.47, 128.44, 128.10, 127.32, 124.34,124.31, 112.47, 21.02, 20.86.

Synthetic Example 22 Method of synthesizing(R)-3,3′-bis[4-(2′,4′,6′-trimethylbipheny1)]-1,1′-binaphthyl-2,2′-diylhydrogenphosphate (GA38)

GA37 (1.91 mmol) obtained in Synthetic example 21 and pyridine (7.8 mL)were put in a two-necked round bottom flask, phosphoryl chloride (2.69mmol) was added dropwise over 7 minutes at room temperature, and thereaction mixture was stirred for additional 2 hours. After that, themixture was heated and refluxed for 1 hour. The reaction mixture wascooled to room temperature. Distillated water (1.6 mL) was addeddropwise and the mixture was heated and refluxed for 1.5 hours. Afterthat, the mixture was cooled to room temperature. Pyridine was distilledaway under a reduced pressure. 6 M hydrochloric acid (15 mL) was addeddropwise, and the mixture was further heated and refluxed for additional2 hours. The reaction mixture was cooled to 0° C. and filtered. Thefiltrate was washed with water and dried. The extract was recrystallizedin ethanol to give GA38 (1.75 mmol, yield: 87%).

¹H-NMR(400 MHz,CDCl₃) δ=8.35(brs,1H), 8.07(s,2H), 7.92(d,2H,J=8.1 Hz),7.51-7.43(m,4H), 7.33-7.24(m,4H), 7.17(d,4H,J=8.1 Hz), 2.32(s,6H),1.98(s,12H).

¹³C-NMR(100 MHz,CDCl₃) δ=142.15, 139.97, 138.73, 136.31, 135.95, 135.72,134.11, 132.19, 131.19, 130.95, 130.06, 128.95, 128.22, 127.90, 127.03,126.08, 125.88, 125.35, 123.07, 20.97, 20.71.

Synthetic Example 23 Method of synthesizing 2-naphthylboronic acid(GA40)

Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in athree-necked round bottom flask and stirred. To the solution,2-bromonaphthalene (13.07 mmol) was added, and the reaction mixture washeated. After that, 2-bromonaphthalene (32.02 mmol) dissolved intetrahydrofuran (30 mL) was added dropwise to the solution. The reactionmixture was heated and refluxed for 4.5 hours. After that, the mixturewas cooled to −78° C. (EtO)₃B (111.66 mmol) was added dropwise over 15minutes. Then, the mixture was warmed to room temperature and stirredfor additional 5 hours. Then, the mixture was cooled to 0° C. Thereaction was quenched by the addition of 1 M hydrochloric acid stirringfor 2 hours. The reaction mixture was extracted with diethyl ether threetimes. The combined extracts was washed with brine and dried overanhydrous sodium sulfate. After the drying, the extract was filtered.Then the filtrate was concentrated. The obtained solid wasrecrystallized in benzene to give GA40 (9 mmol, yield: 77%).

¹H-NMR(400 MHz,CDCl₃) δ=8.91(s,1H), 8.35(d,1H,J=8.2 Hz), 8.11(d,1H,J=7.3Hz), 8.01(d,1H,J=8.2 Hz), 7.96(d,1H,J=7.3 Hz), 7.64(m,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=137.89, 135.88, 132.91, 130.68, 129.12, 127.89,127.67, 127.37, 126.05.

Synthetic Example 24 Method of synthesizing2-(4-Bromonaphthyl)naphthalene (GA42)

GA40 (4.98 mmol) obtained in Synthetic example 23, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, GA31 (15.0 mmol) obtained inSynthetic example 18 was added, and the reaction mixture was heated andrefluxed for 22 hours. The reaction mixture was cooled to roomtemperature. Dioxane was distilled away under a reduced pressure. Afterthe addition of 1 M hydrochloric acid, the mixture was extracted withdichloromethane three times. The combined extracts were washed with 1 Mhydrochloric acid twice and with brine once, and dried over anhydroussodium sulfate. After the drying, the extract was filtered. The filtratewas concentrated to give a solid, which was deprotected in the sameprocedure as that in Synthetic example 6. The obtained solid wasseparated and purified by means of column chromatography to give GA42(7.02 mmol, yield: 79%).

Rf=0.6(Hexane).

¹H-NMR(400 MHz,CDCl₃) δ=8.01(s,1H), 7.93-7.85(m,3H), 7.77-7.68(m,1H),7.60-7.59(m,4H), 7.57-7.48(m,2H).

¹³C-NMR(100 MHz,CDCl3) δ=140.03, 137.29, 133.59, 132.71, 131.95, 128.97,128.62, 128.18, 127.66, 126.47, 126.17, 125.72, 125.13, 121.64, 106.35.

Synthetic Example 25 Synthesis of(R)-3,3′-bis(4-naphthalen-2-yl-phenyl)-1,1′-binaphthol (GA44)

GA16 (4.98 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (14.9 mmol), Pd(PPh₃)₄ (0.24 mmol), degassed dioxane (33mL), and distillated water (11 mL) were put in a three-necked roundbottom flask and stirred. To the solution, GA42 (15.0 mmol) obtained inSynthetic example 24 was added, and the reaction mixture was heated andrefluxed for 22 hours. The reaction mixture was cooled to roomtemperature. Dioxane was distilled away under a reduced pressure. Afterthe addition of 1 M hydrochloric acid, the mixture was extracted withdichloromethane three times. The combined extracts was washed with 1 Mhydrochloric acid twice and with brine once, and dried over anhydroussodium sulfate. After the drying, the extract was filtered, and thefiltrate was concentrated. A obtained solid was separated and purifiedby means of silica gel column chromatography (Hexane:CH₂Cl₂=2:1 toHexane:CH₂Cl₂=1:1). However, since GA42 could not completely be removed,it was separated and purified again by means of neutral alumina columnchromatography (benzene to ethyl acetate) to give GA44 (1.61 mmol,yield: 57%).

Rf=0.5.

¹H-NMR(400 MHz,CDCl₃) δ=8.11(s,4H), 7.96-7.23(m,18H), 7.52-7.23(m,10H),5.44(s,2H).

¹³C-NMR(100 MHz,CDCl₃) δ=150.28, 140.44, 138.02, 136.52, 133.68, 132.96,132.69, 131.42, 130.25, 130.12, 129.53, 128.49, 128.22, 127.65, 127.46,127.42, 126.32, 125.99, 125.80, 125.47, 124.43, 124.27, 112.31.

Synthetic Example 26 Synthesis of(R)-3,3′-bis(4-naphthalen-2-yl-phenyl)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate (GA45)

GA44 (1.91 mmol) obtained in Synthetic example 25 and pyridine (7.8 mL)were put in a two-necked round bottom flask. To the solution, phosphorylchloride (2.69 mmol) was added dropwise over 7 minutes at roomtemperature, and the reaction mixture was stirred for additional 2hours. After that, the mixture was heated and refluxed for 1 hour. Thereaction mixture was cooled to room temperature. Distillated water (1.6mL) was added dropwise, and the mixture heated and refluxed for 1.5hours. After that, the mixture was cooled to room temperature. Pyridinewas distilled away under a reduced pressure. 6 M hydrochloric acid (15mL) was added dropwise, and then the mixture was heated and refluxed foradditional 2 hours. The reaction mixture was cooled to 0° C. andfiltered. The filtrate was washed with water and dried. The solid wasrecrystallized in Toluene/Hexane to give GA45 (1.15 mmol, yield: 79%).

¹H-NMR(400 MHz,CDCl₃) δ=8.06(s,2H), 7.95(d,4H,J=7.5 Hz), 7.90(d,4H,J=8.1Hz), 7.85-7.81 (m,6H), 7.68-7.64(m,6H), 7.48-7.45(m,6H), 7.40(d,2H,J=8.8Hz), 7.28(m,12H), 7.15(brs,1H).

¹³C-NMR(100 MHz,CDCl₃) δ=146.10, 141.45, 139.12, 137.61, 136.98, 133.94,133.50, 132.45, 132.29, 131.19, 130.73, 130.59, 128.31, 128.17, 127.50,127.04, 126.77, 126.12, 125.78, 125.48, 125.34, 125.19, 123.18.

Synthetic Example 27 Synthesis of(R)-2,2′-bis(methoxymethyloxy)-1,1′-binaphthyl (GB06)

NaH (28.95 mmol) was put in a three-necked round bottom flask and washedwith anhydrous diethyl ether twice. To the flask, (R)-BINOL (12.62 mmol)and DMF 60 ml were added, and the reaction mixture was stirred at 0° C.for 30 minutes. Subsequently, Methoxymethyl chrolide (MOMCl; 31.89 mmol)was added dropwise at 0° C. over 10 minutes. After being warmed to roomtemperature, the mixture was stirred for additional 1 hour. The reactionwas quenched by the addition of water and 1 M hydrochloric acid andstirring for a few minutes. The mixture was extracted with ethyl acetatethree times. The extract was washed with a saturated aqueous sodiumchloride solution, and dehydrated over anhydrous sodium sulfate. Afterthe dehydration, the extract was filtered. Then the solvent wasdistilled away from the filtrate under a reduced pressure to give GB06(12.59 mmol, quant.).

Synthetic Example 28 Synthesis of(R)-2,2′-bis(methoxymethyloxy)-3,3′-dibromo-1,1′-binaphthyl (GB07)

GB06 (12.6 mmol) obtained in Synthetic example 27 and diethyl ether 200mL were put in a three-necked round bottom flask. n-BuLi (37.4 mmol) wasadded at room temperature, and the reaction mixture stirring for 3hours. The reaction mixture was cooled to 0° C. A solution prepared bydissolving CF₂Br—CF₂Br (37.4 mmol) in THF 50 mL was added dropwise.After the adding dropwise, the mixture was warmed to room temperatureand stirred for additional 4 hours. After that, the reaction wasquenched by the addition of a saturated aqueous sodium chloridesolution. The mixture was extracted with diethyl ether three times. Theextract was washed with a saturated aqueous sodium chloride solution,and dehydrated over anhydrous sodium sulfate. After the dehydration, theextract was filtered. After distilling the solvent away under a reducedpressure, the filtrate was purified by means of column chromatography(Hexane:AcOEt=5:1) to give GB07 (12.13 mmol, yield: 96%).

Synthetic Example 29 Synthesis of GB08 (Formula (19))

p-Bromoanisole (26.46 mmol) and THF 20 mL were put in a three-neckedround bottom flask and cooled to −78° C. n-BuLi (29.83 mmol) was addeddropwise thereto over 12 minutes, and the reaction mixture was stirredat −78° C. for additional 1 hour. After that, triethyl borate (29.45mmol) was added dropwise to the reaction mixture over 9 minutes, and themixture was stirred at −78° C. for 1.5 hours. After the stirring, thereaction was quenched at −78° C. by the addition of a saturated aqueousammonium chloride solution. After being warmed to room temperature, 100ml of water was added, and the mixture was extracted with diethyl ether.The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, anddehydrated over anhydrous sodium sulfate. After the dehydration, theextract was filtered. After distilling the solvent away under a reducedpressure, the filtrate was crystallized in water to give GB08 (7.57mmol, yield: 28%) represented by formula (19).

Synthetic Example 30 Synthesis of(R)-3,3′-bis(p-methoxyphenyl)-1,1′-binaphthol (GB11)

After Pd(PPh₃)₄ (0.083 mmol) and DME 6 mL were put in a three-neckedround bottom flask, a solution prepared by dissolving GB07 (2.52 mmol)obtained in Synthetic example 28 in DME 8 mL was added. Then, GB08 (7.57mmol) obtained in Synthetic example 29 and 2.4 mL of a 4 M aqueoussodium carbonate solution were further added, and the reaction mixturewas stirred for 18 hours under reflux. Then, the mixture was cooled toroom temperature and filtered. From the filtrate, the solvent wasdistilled away under a reduced pressure. After the concentration, asuitable amount of dichloroethane was added, and the mixture was washedwith water and a saturated aqueous sodium chloride solution, anddehydrated over anhydrous sodium sulfate. After the dehydration, themixture was filtered. Then the solvent in the filtrate was distilledaway under a reduced pressure. The dried product, 10 ml of THF, and 0.4ml of concentrated hydrochloric acid were put in a two-necked roundbottom flask and stirred at 50° C. for 2 hours. The mixture was cooledto room temperature. The-reaction was quenched at 0° C. by the additionof a saturated aqueous sodium hydrogen carbonate solution. After that,the mixture was extracted with diethyl ether three times. The extractwas washed with a saturated aqueous sodium chloride solution, anddehydrated over anhydrous sodium sulfate. After the dehydration, theextract was filtered. After distilling the solvent away under a reducedpressure, the filtrate was purified by means of column chromatography(Hexane:AcOEt=4:1) to give GB11 (1.14 mmol, yield: 45%).

¹H-NMR(400 MHz,CDCl₃) δ=3.85(6H,S), 5.35(2H,S), 7.00(4H,d), 7.18(2H,d),7.27(2H,dd), 7.35(2H,dd), 7.64(4H,d), 7.87(2H,d), 7.96(2H,s)

Synthetic Example 31 Synthesis of(R)-3,3′-bis(p-methoxyphenyl)-1,1′-binaphthyl-2,2′-diylhydrogen-phosphate (GB15)

GB11 (1.02 mmol) obtained in Synthetic example 30 and 1.4 ml of pyridinewere put in a two-necked round bottom flask. POCl₃ (1.45 mmol) was addeddropwise over 3 minutes, and the reaction mixture was stirred for 1.5hours under refluxing. The reaction mixture was cooled to roomtemperature, and water (150 μL) was added over 5 minutes. Then, afterstirring for 2 hours under refluxing, the mixture was cooled to roomtemperature. From the reaction mixture, pyridine was distilled awayunder a reduced pressure. After that, 6 M hydrochloric acid (7 mL) wasadded over 10 minutes, and the mixture was stirred for 2.5 hours underrefluxing. The mixture was cooled to 0° C. and filtered. The filteredresidue was washed with water and crystallized in ethanol to give GB15(0.37 mmol, yield: 37%).

Synthetic Example 32 Synthesis of(R)-3,3′-bis[4-(trifluoromethyl)phenyl]-1,1′-binaphthol (GB14)

GA16 (3.73 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (11.03 mmol), Pd(PPh₃)₄ (0.14 mmol), 1,4-dioxane 24 ml, and8 mL of water were put in a three-necked round bottom flask and stirred.To the solution, 4-Bromobenzotrifluoride (12.14 mmol) was added dropwiseover 10 minutes. The solution was refluxed for 24 hours. After that,1,4-dioxane was distilled away under a reduced pressure, and thendichloromethane was added. The mixture was washed with 1 M hydrochloricacid and a saturated aqueous sodium chloride solution, and dehydratedover anhydrous sodium sulfate. The above product and 100 mL ofdichloromethane were put in a three-necked round bottom flask and thencooled to 0° C. BBr₃ (16.76 mmol, a 1 M dichloromethane solution) wasadded dropwise. After completing the adding dropwise, the mixture wasstirred at room temperature for 8.5 hours and then cooled again to 0° C.The reaction was quenched by the addition of 120 ml of water. Themixture was washed with water and a saturated aqueous sodium chloridesolution followed by dehydration over anhydrous sodium sulfate. Thesolvent was distilled away under a reduced pressure. The residue waspurified by means of column chromatography (Hexane:AcOEt=5:1) to giveGB14 (2.29 mmol, yield: 61%).

Synthetic Example 33 Synthesis of(R)-3,3′-bis[4-(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diylhydrogenphosphate (GB16)

GB14 (1.02 mmol) obtained in Synthetic example 32 and 1.4 mL of pyridinewere put in a two-necked round bottom flask. POCl₃ (1.45 mmol) was addeddropwise over 3 minutes, and the reaction mixture was refluxed for 1.5hours. The reaction mixture was cooled to room temperature. Water (150μL) was added over 5 minutes. After that, the mixture was refluxed for 2hours, and cooled to room temperature. Then, pyridine was distilled awayfrom the reaction mixture under a reduced pressure. 6 M hydrochloricacid (7 mL) was added over 10 minutes followed by refluxing for 2.5hours. The mixture was cooled and purified by means of silica gel columnchromatography containing triethylamine, and then made into a free saltform with 6 M hydrochloric acid to give GB16.

Synthetic Example 34 Synthesis of(R)-3,3′-bis(4-nitrophenyl)-1,1′-binaphthol (GC01)

GA16 (4 mmol) obtained in Synthetic example 13, barium hydroxideoctahydrate (12 mmol), Pd(PPh₃)₄ (0.28 mmol), 24 mL of 1,4-dioxane, and8 mL of water were put in a three-necked round bottom flask and stirred.To the solution, 1-Bromo-4-nitrobenzene (10 mmol) was added dropwise,and the reaction mixture was refluxed for 25 hours. After that,1,4-dioxane was distilled away under a reduced pressure, and thendichloromethane was added. The mixture was washed with 1 M hydrochloricacid and a saturated aqueous sodium chloride solution, and dehydratedover anhydrous sodium sulfate. The above product and 100 mL ofdichloromethane were put in a three-necked round bottom flask, which wascooled to 0° C. BBr₃ (18 mmol, a 1 M dichloromethane solution) was addeddropwise. After completion of the addition dropwise, the mixture wasstirred at room temperature for 8.5 hours and cooled again to 0° C. Thereaction was quenched by the addition of 120 mL of water. The mixturewas washed with water and a saturated aqueous sodium chloride solution,and dehydrated over anhydrous sodium sulfate. The solvent was distilledaway under a reduced pressure. The residue was purified by means ofcolumn chromatography (Hexane:AcOEt=5:1) to give GC01 (yield: 82%).

Synthetic Example 35 Synthesis of(R)-3,3′-bis(4-nitrophenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen-phosphate(GC02)

GC01 (1 mmol) and 1.4 mL of pyridine were put in a two-necked roundbottom flask. POCl₃ (1.4 mmol) was added dropwise over 3 minutes, andthe reaction mixture was stirred at room temperature for 2 hours. To thereaction mixture, water (150 μL) was added, and the mixture was stirredfor additional 30 minutes. After that, pyridine was distilled away fromthe reaction mixture under a reduced pressure. After that, 6 Mhydrochloric acid (7 mL) was added, and the mixture was refluxed for 2hours. The mixture was cooled and purified by means of silica gel columnchromatography containing triethylamine, which was made into a free saltform with 6 M hydrochloric acid. The free salt form was dissolved in asmall amount of dichloromethane, and n-hexane was added to precipitateand give GC02 (yield: 62%).

¹H-NMR(400 MHz,CDCl₃) δ=8.01(d,2H,J=8.2 Hz), 7.97(s,2H), 7.92(d,4H,J=8.1Hz), 7.60-7.55(m,6H), 7.46-7.21(m,4H).

Synthetic Example 36 Synthesis of(R)-3,3′-diphenyl-2,2′-dimethoxy-1,1′-binaphthyl (GC03)

GA16 (4 mmol) obtained in Synthetic example 13, Ni(PPh₃)₂Cl₂ (0.32 mmol)and diethyl ether (40 mL) were put in a three-necked round bottom flask.Phenyl MgBr was added dropwise, which had been prepared independently,at room temperature followed by heating and refluxing for 26.5 hours.The reaction mixture was cooled to 0° C., to which was added 1 Mhydrochloric acid followed by stirring to quench the reaction. Thereaction mixture was extracted with diethyl ether three times. Thecombined extracts was washed with brine and dried over anhydrous sodiumsulfate. After the drying, the extract was filtered. The concentratedfiltrate was separated and purified by means of column chromatography togive GC03 (yield: 89%).

Synthetic Example 37 Synthesis of (R)-3,3′-diphenyl-1,1′-binaphthol(GC04)

GC03 obtained in Synthetic example 36 was subjected to the samedeprotection operation as that in Synthetic example 6 to give GC04.

Synthetic Example 38 Synthesis of(R)-6,6′-dibromo-3,3′-diphenyl-1,1′-binaphthol (GC05)

GC04 (1 mmol) obtained in Synthetic example 37 was dissolved indichloromethane and cooled to −78° C. Bromine (2.1 mmol) was addeddropwise, the reaction mixture was stirred for 2.5 hours. The reactionmixture was warmed to room temperature. The reaction was quenched by theaddition of an aqueous sodium thiosulfate solution. The solution wasextracted with diethyl ether. The extract was washed with a saturatedaqueous sodium chloride solution, and dehydrated over anhydrous sodiumsulfate. After the dehydration, the extract was filtered. The solventwas distilled away from the filtrate under a reduced pressure to giveGC05 (yield: 66%).

Synthetic Example 39 Synthesis of(R)-6,6′-dibromo-3,3′-diphenyl-1,1′-binaphthyl-2,2′-diylhydrogen-phosphate (GC06)

GC05 (1 mmol) obtained in Synthetic example 38 and 1.4 mL of pyridinewere put in a two-necked round bottom flask. POCl₃ (1.4 mmol) was added,and the reaction mixture was stirred at room temperature for 2 hours. Tothe reaction, water and sodium hydrogencarbonate were added, and themixture was additionally stirred. After that, pyridine was distilledaway from the reaction mixture under a reduced pressure. 6 Mhydrochloric acid (7 mL) was added, and the mixture was refluxed for 2hours. The mixture was cooled, purified by means of silica gel columnchromatography containing triethylamine, which was made into a free saltform with 6 M hydrochloric acid. The free salt form was dissolved in asmall amount of dichloromethane, and n-hexane was added to precipitateand give GC06 (yield: 57%).

Synthetic Example 40 Synthesis of silylenolate MK01 (Formula (20))

Tetrahydrofuran (20 mL) and diisopropylamine (30 mmol) were put in athree-necked round bottom flask (200 mL) and stirred at 0° C. Afterthat, n-BuLi (30 mmol) was added dropwise over 5 minutes, and thereaction mixture was stirred for 30 minutes. The mixture was cooled to−78° C. Hexamethylphosphoramide (HMPA; 5.0 mL) and methyl isobutyrate(30.1 mmol) were added dropwise over 5 minutes. The mixture was stirredfor 30 minutes. Trimethylsilyl chloride (TMSCl, 35.4 mmol) was added at−78° C. The mixture was warmed to room temperature and stirred for 1hour, and then cooled to 0° C. The reaction was quenched by the additionof sodium hydrogencarbonate. The reaction mixture was extracted withdiethyl ether three times. The combined extracts was washed with brineand dried over anhydrous sodium sulfate. After the drying, the extractwas filtered. After removing the solvent, the filtrate was subjected toreduced-pressure distillation (1600 Pa, 69-71° C.) to give silylenolateMK01 represented by formula (20) below.

Synthetic Example 41 Synthesis of silylenolate MK02

The procedure of Synthetic example 40 was repeated except that TMSCl waschanged to t-Butyldimethylsilyl chloride (TBSCl) to give MK02.

Synthetic Example 42 Synthesis of silylenolate MK03

The procedure of Synthetic example 40 was repeated except that methylisobutyrate was changed to isopropyl isobutyrate to give MK03.

Synthetic Example 43 Synthesis of silylenolate MK04

The procedure of Synthetic example 40 was repeated except that methylisobutyrate was changed to methyl acetate to give MK04.

Synthetic Example 44 Synthesis of imine MI01 (Formula (21))

Imine MI01 represented by formula (21) below was synthesized fromBenzaldehyde and 2-Aminophenol.

Synthetic Example 45 Synthesis of(R)-3,3′-Bis[3,5-di(trifluoromethyl)phenyl]-1,1′-binaphthol (GC07)

Pd(PPh₃)₄ (0.15 mM, 0.06 eq.), dimethoxyethane (15 mL),3,5-Bis(trifluoromethyl)bromobenzene (7.54 mM, 3.0 eq.) were put, inthis order, in a dried three-necked round bottom flask (100 mL) undernitrogen atmosphere and stirred for 10 minutes.(R)-3,3′-Bis(dihydroxyborane)-2,2′-dimethoxy-1,1′-binaphthyl (2.56 mM)having been diluted with ethanol and 2 N sodium carbonate solution (7.6mM, 3.0 eq.) were added, and the reaction mixture was heated andrefluxed for 18.5 hours. After that, the mixture was cooled to roomtemperature, and dimethoxyethane was distilled away under a reducedpressure. Then, the residue was dissolved in dichloromethane and 1 Nhydrochloric acid, and was extracted with dichloromethane three times.The combined dichloromethane extracts was sequentially washed with 1 Nhydrochloric acid and brine, and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. From the product obtained byconcentrating the filtrate, a methoxy group was removed. The deprotectedproduct was purified by means of column chromatography to give GC07(formula (22) below, 1.4 g, 2.01 mM, 79%).

[α]_(D) ²⁶: 45.3(c1.06,CHCl₃).

IR(CHCl₃): 3522, 1622, 1597, 1502, 1474, 1462, 1427, 1377, 1358, 1335,1281, 1236, 1182, 1140, 1036, 989, 897, 845 cm⁻¹.

Rf=0.3(Hexane:CH₂Cl₂=4:1).

¹H-NMR(400 MHz,CDCl₃) δ=8.24(s,4H), 8.12(s,2H), 8.00(d,2H,J=7.9 Hz),7.91(s,2H), 7.50-7.40(m,4H), 7.24-7.22(m,2H), 5.38(s,2H).

¹⁹F-NMR(376 MHz,CDCl₃) δ=99.01(s).

¹³C-NMR(100 MHz,CDCl₃) δ=149.86, 139.47, 133.24, 132.35, 132.09, 131.76,131.42, 131.09, 129.85,129.46, 128.90, 128.67, 127.71, 127.49, 125.21,124.78, 123.97, 122.06, 121.33, 119.35, 111.75.

Anal. Calcd for: C,60.86; H,2.55; found: C,61.03; H,2.25.

Synthetic Example 46 Synthesis of(R)-3,3′-Bis[3,5-di(trifluoromethyl)phenyl]-1,1′-binaphthyl phosphate(GC08)

Synthesis was conducted in the same procedure as that in the method ofobtaining GA15 from GA14. The obtained crude product was recrystallizedin dichloromethane/n-hexane, but the recrystallized product includedimpurities. Thus, it was dissolved in ethanol and reprecipitated with 6N hydrochloric acid to give (GC08) (formula (23) below, 0.9 g, 1.14 mM,73%).

[α]_(D) ²⁶: −197.5(c0.97,CHCl₃).

IR(CHCl₃): 1620, 1501, 1474, 1379, 1325, 1281, 1246, 1178, 1140, 1109,1084, 1024, 988, 964, 891, 870, 867 cm⁻¹.

¹H-NMR(400 MHz,CDCl₃) δ=8.01(s,8H), 7.61-7.58(m,4H), 7.42-7.39(m,4H).

³¹P-NMR(400 MHz,CDCl₃) δ=4.61.

¹⁹F-NMR(376 MHz,CDCl₃) δ=96.63(s).

¹³C-NMR(100 MHz,CDCl₃) δ=143.57, 143.48, 138.55, 132.29, 132.00, 131.94,131.61, 131.39, 131.27, 131.11, 131.08, 130.94, 129.86, 128.65, 127.56,127.20, 127.06, 126.77, 124.49, 122.49, 122.47, 121.77, 121.54, 119.06,96.12.

Anal. Calcd for: C,55.97; H,2.22; found: C,55.96; H,2.13.

Synthetic Example 47 Synthesis of(R)-3,3′-bis(3,5-dinitrophenyl)-1,1′-binaphthyl phosphate (GC09)

The procedure of Synthetic example 45 was repeated except that3,5-dinitrobromobenzene was employed to synthesize a compound to which a3,5-dinitrophenyl group was bonded. Then, the procedure of Syntheticexample 46 was repeated to synthesize phosphoric acid ester body GC09(formula (24)).

Synthetic Example 48 Synthesis of(R)-3,3′-Bis(2,4,6-triisopropylphenyl)-2,2′-hydroxy-1,1′-dinaphthyl(GC10)

GA07 (5.0 mM), Ni(PPh₃)₂Cl₂ (0.51 mM, 0.1 eq.) and diethyl ether (50 mL)were put, in this order, in a dried three-necked round bottom flask (200mL) under nitrogen atmosphere and stirred. 2,4,6-Triisopropylphenyl MgBrprepared separately was added dropwise over 7 minutes or more at roomtemperature. After the adding dropwise, the mixture was stirred foradditional 10 minutes, and was heated and refluxed for 24 hours. Afterthat, the mixture was cooled to 0° C. The reaction was quenched by theaddition of 1 N hydrochloric acid and stirring. The reaction mixture wasextracted with diethyl ether three times. The combined diethyl etherextracts was washed with brine and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. The filtrate wasconcentrated to give a crude product, which was used in the subsequentstep without purification.

The crude product obtained in the previous step and dichloromethane (135mL) were put, in this order, in a dried three-necked round bottom flask(300 mL) under nitrogen atmosphere and stirred at 0° C. A mixtureprepared by diluting boron tribromide (23.28 mM, 4.6 eq.) withdichloromethane (23 mL) was added dropwise over 15 minutes or more.After that, the mixture was warmed to room temperature and stirred for16 hours. After the stirring, the mixture was cooled to 0° C. Thereaction was quenched by the addition of water. The reaction mixture wasextracted with dichloromethane three times. The combined dichloromethaneextracts was washed with brine and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. The filtrate wasconcentrated to give a crude product, which was separated and purifiedby means of column chromatography to give GC10 (2.04 mM, 41%).

[α]_(D) ²⁷ 88.8(c3.03,THF), literature value [α]_(D) 88.0(c3.00,THF).

Rf=0.2(Hexane:CH₂Cl₂=6:1).

¹H NMR(400 MHz,CDCl₃) δ=7.87(d,2H,J=8.2 Hz), 7.77(s,2H),7.40-7.12(m,10H), 4.92(s,2H), 2.99-2.91(m,2H), 4.92(dd,1H,J=2.7,8.4 Hz),4.44(d,1H,J=2.7 Hz), 3.89(s,3H), 3.69(s,3H), 0.89(s,9H).

¹³C NMR(100 MHz,CDCl₃) δ=150.63, 149.12, 147.80, 147.74, 133.46, 130.63,130.37, 129.10, 129.04, 128.227, 126.61, 124.52, 123.76, 121.22, 121.15,113.11, 34.35, 30.89, 30.84, 24.31, 24.29, 24.07, 24.01, 23.92, 23.73.

Anal. Calcd for: C,86.91; H,8.46; found: C,86.83; H, 8.31.

Synthetic Example 49 Synthesis of(R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate (GC11)

GC10 was subjected to the same procedure as that in Synthetic example12. A crude product obtained in the procedure was separated and purifiedby means of column chromatography to give GC11 (1.38 mM, 95%).

[α]_(D) ²⁶−59.4(c1.06,CHCl₃).

IR(CHCl₃) 2964, 2932, 2870, 1626, 1607, 1568, 1491, 1462, 1412, 1383,1362, 1317, 1246, 1196, 1151, 1055, 959, 858, 847 cm⁻¹.

Rf=0.7(Hexane:CH₂Cl₂=10:1).

¹H NMR(400 MHz,CDCl₃) δ=7.88-7.84(m,2H), 7.80(s,2H), 7.45-7.41(m,2H),7.32-7.25(m,4H), 7.02(s,2H), 6.95(s,2H), 2.94-2.82(m,4H),2.71-2.65(m,2H), 1.23(d,12H,J=6.8 Hz), 1.13-1.10(m,12H), 1.03(d,6H,J=6.8Hz), 0.92(d,6H,J=6.8 Hz).

³¹P NMR(400 MHz,CDCl₃) δ=4.02.

¹³C NMR(100 MHz,CDCl₃) δ=148.06, 147.56, 147.47, 147.33, 142.69, 142.22,132.92, 132.67, 131.92, 130.50, 128.02, 127.20, 125.76, 125.64, 124.85,122.48, 120.84, 119.95, 34.14, 30.91, 30.72, 26.33, 24.93, 24.15, 24.02,23.50, 23.31.

Anal. Calcd for: C,79.76; H,7.63; found: C,79.52; H,7.87.

Synthetic Example 50 Synthesis of(R)-5,5′,6,6′,7,7′,8,8′-Octahydro-1,1′-bi-2-naphthol (CD01)

(R)-BINOL (70.52 mM), platinum oxide (1.15 mM), and acetic acid (25 mL)were put in an autoclave in this order and stirred under a hydrogenatmosphere of 6.8 atoms at room temperature for 3 days. The reaction wasquenched by the addition of water and dichloromethane. The reactionmixture was extracted with dichloromethane three times. Thedichloromethane extract was washed with water once and with a saturatedaqueous sodium hydrogen carbonate solution twice, and dried overanhydrous sodium sulfate. After the drying, the extract was filtered.The filtrate was concentrated to give CD01 (70.74 mM, quant., formula(25) below).

[α]_(D) ²⁶ 47.1(c 1.04,CHCl₃).

¹H NMR(400 MHz,CDCl₃) δ=7.06(d,2H,J=8.2 Hz), 6.82(d,2H,J=8.2 Hz),4.60(s,2H), 2.75(t,4H,J=6.2 Hz), 2.33-2.25(m,2H), 2.19-2.12(m,2H),1.77-1.64(m,8H).

¹³C NMR(100 MHz,CDCl₃) δ=151.35, 137.12, 131.01, 130.08, 118.81, 112.93,29.20, 27.08, 22.98, 22.92.

Synthetic Example 51 Synthesis of(R)-5,5′,6,6′,7,7′,8,8′-Octahydro-1,1′-bi-2-naphthyl phosphate (GD02)

The same procedure as that in the method of synthesizing GC02 wasrepeated to synthesize GD02 from GD01. After the synthesis, the crudewas reprecipitated in methanol and water to give GD02 (formula (26)below, 1.35 mM, yield: 57%).

[α]_(D) ²⁵−239.7(c1.01,EtOH)

¹H NMR(400 MHz,CDC₃) δ=7.11(d,2H,J=8.4 Hz), 7.06(d,2H,J=8.4 Hz),4.82(brs,1H), 2.86-2.63(m,6H), 2.31-2.24(m,2H), 1.82-1.77(m,6H),1.57-1.52(m,2H).

³¹P NMR(400 MHz,CDCl₃) δ=2.04.

¹³C NMR(100 MHz,CDCl₃) δ=146.35, 138.27, 135.46, 129.93, 126.08, 118.11,29.09, 27.79, 22.44, 22.29.

Anal. Calcd for: C,67.41; H,5.94; found: C,67.62; H,6.01.

Synthetic Example 52 Synthesis of(R)-3,3′-Dibromo-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2-naphthol (GD03)

GD01 (3.48 mM) and dichloromethane (20 mL) were put, in this order, in adried three-necked round bottom flask (100 mL) under nitrogen atmosphereand stirred. Subsequently, bromine (8.53 mM) was added dropwise over 16minutes at room temperature. Then, after stirring the mixture at roomtemperature for 16.5 hours (disappearance of GD01 was checked by meansof TLC), the mixture was cooled to 0° C. The reaction was quenched bythe addition of a saturated aqueous sodium sulfite solution. Thereaction mixture was extracted with dichloromethane three times. Thecombined dichloromethane extracts was washed with brine and dried overanhydrous sodium sulfate. After the drying, the extract was filtered.The filtrate was concentrated to give GD03 (3.64 mM, quant.).

¹H NMR(400 MHz,CDCl₃) δ=7.28(s,2H), 5.11(s,2H), 2.74-2.73(m,4H),2.32-2.26(m,2H), 2.12-2.06(m,2H), 1.76-1.61(m,8H).

Synthetic Example 53 Synthesis of(R)-3,3′-Dibromo-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-methoxymethyl-1,1′-binaphthyl(GD04)

Sodium hydride (24.10 mM, having been washed with diethyl ether) and DMF(40 mL) were put, in this order, in a dried three-necked round bottomflask (200 mL) under nitrogen atmosphere and stirred at 0° C. GD03 (9.73mM) dissolved in DMF (30 mL) was added, and the reaction mixture wasstirred for 20 minutes. Subsequently, MOMCl (25.02 mM) was addeddropwise over 3 minutes at 0° C. Two hours after warming the mixture toroom temperature (disappearance of GD03 was checked by means of TLC),the mixture was cooled to 0° C. The reaction was quenched by theaddition of water, ethyl acetate and 1 N hydrochloric acid. The reactionmixture was extracted with ethyl acetate three times. The combined ethylacetate extracts was washed sequentially with 1 N hydrochloric acid andbrine and dried over anhydrous sodium sulfate. After the drying, theextract was filtered. The filtrate was concentrated to give GD04 (9.88mM, quant.).

¹H NMR(400 MHz,CDCl₃) δ=7.32(s,2H), 4.93(d,2H,J=5.7 Hz), 4.83(d,2H,J=5.7Hz), 2.86(s,6H), 2.76-2.71(m,4H), 2.44-2.38(m,2H), 2.14-2.09(m,2H),1.75-1.60(m,8H).

Synthetic Example 54 Synthesis of(R)-3,3′-Diphenyl-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthol (GD05)

Barium hydroxide octahydrate (12.02 mM, 3.0 eq.), phenylboric acid(12.01 mM, 3.0 eq.), Pd(PPh₃)₄ (0.25 mM, 0.06 eq.), GD04 (4.02 mM),dioxane (27 mL), and distillated water (9 mL) were put, in this order,in a dried three-necked round bottom flask (100 mL) under nitrogenatmosphere and heated and refluxed for 3 hours. After that, the mixturewas cooled to room temperature, and dioxane was distilled away under areduced pressure. Then, dichloromethane and 1 N hydrochloric acid wereadded. The reaction mixture was extracted with dichloromethane threetimes. The combined dichloromethane extracts was washed with 1 Nhydrochloric acid and brine, and dried over anhydrous sodium sulfate.After the drying, the extract was filtered. The filtrate wasconcentrated to give a solid. Ethanol (50 mL) and concentratedhydrochloric acid (12 mL) were added to the solid, and the reactionmixture was heated and refluxed for 10 hours. After the refluxing,ethanol was distilled away from the reaction mixture under a reducedpressure. The mixture was extracted with dichloromethane three times.The combined dichloromethane extracts was washed with brine and driedover anhydrous sodium sulfate. After the drying, the extract wasfiltered. The filtrate was concentrated to give a solid, which wasseparated and purified by means of column chromatography to give GD05(2.23 mM, 55%).

[α]_(D) ²⁵−19.0(c0.40,CHCl₃), literature value [α]_(D)²⁵−29.3(c0.41,CHCl₃).

Rf=0.2(Hexane:Ethyl acetate=15:1)

¹H NMR(400 MHz,CDCl₃) δ=7.61-7.58(m,4H), 7.45-7.40(m,4H),7.34-7.29(m,2H), 7.15(s,2H), 4.91(s,2H), 2.82-2.78(m,4H),2.44-2.38(m,2H), 2.30-2.22(m,2H), 1.76-1.74(m,8H).

¹³C NMR(100 MHz,CDCl₃) δ=147.92, 137.78, 136.44, 131.59, 130.08, 129.09,128.26, 126.97, 125.92, 120.04, 29.37, 27.28, 23.18, 23.16.

Synthetic Example 55 Synthesis of(R)-5,5′,6,6′,7,7′,8,8′-Octahydro-3,3′-bisphenyl-1,1′-binaphthylphosphate (GD06)

The same procedure as that in the method of synthesizing GC02M wasrepeated to synthesize GD06 from GD05. By means of columnchromatography, the obtained crude product was separated from thestarting material (dichloromethane as the solvent), and then wasseparated and purified with methanol to give GD06 (formula (27) below,1.18 mM, 75%).

[α]_(D) ²⁵−211.3(c0.99,CHCl₃).

IR(CHCl₃) 3009, 2939, 2862, 1603, 1501, 145, 1416, 1275, 1225, 1215,1196, 1157, 1138, 1020, 955, 908, 858 cm⁻¹.

¹H NMR(400 MHz,CDCl₃) δ=7.40(d,4H,J=7.2 Hz), 7.13-7.01(m,8H),4.74(brs,1H), 2.89-2.64(m,6H), 2.37-2.30(m,2H), 1.79-1.59(m,2H).

³¹P NMR(400 MHz,CDCl₃) δ=0.33.

¹³C NMR(100 MHz,CDCl₃) δ=143.41, 143.29, 137.24, 137.05, 134.46, 131.53,130.79, 129.37, 127.97, 127.20, 126.88, 29.29, 27.92, 22.80, 22.69.

Anal. Calcd for: C,75.58; H,5.75; found: C,75.39; H,5.62.

Synthetic Example 56 Synthesis of(R)-5,5′,6,6′,7,7′,8,8′-Octahydro-2,2′-methoxymethylnaphthol (GD07)

GD01 was subjected to the same procedure as that for GD04 to bemethoxymethylated to give GD07 (7.46 mM, quant.) (oil).

¹H NMR(400 MHz,CDCl₃) δ=7.04(d,2H,J=8.7 Hz), 6.98(d,2H,J=8.7 Hz),5.02(dd,2H,J=1.3,6.6 Hz), 4.96(dd,2H,J=1.3,6.6 Hz), 3.29(s,6H),2.78-2.75(m,4H), 2.34-2.26(m,2H), 2.14-2.08(m,2H), 1.74-1.64(m,8H).

¹³C NMR(100 MHz,CDCl₃) δ=151.97, 136.61, 130.76, 128.69, 126.93, 112.58,94.67, 55.64, 29.52, 27.37, 23.30, 23.20.

Synthetic Example 57 Synthesis of(R)-2,2′-Dihydroxy-3,3′-bis(4-nitrophenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-dinaphthyl(GD09)

GD07 (2.68 mM) and diethyl ether (50 mL) were put in a driedthree-necked round bottom flask (200 mL) under nitrogen atmosphere.n-Butyllithium (10.99 mM) was added dropwise with stirring at roomtemperature over 8 minutes. After 3 hours, thus prepared mixture wasadded dropwise to a solution of2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.83 mM) andTHF (18 mL), which had been prepared separately, with a cannuler over 24minutes at −78° C. The mixture was warmed to room temperature, and wasstirred for 16 hours. After that, the reaction mixture was filtered overcelite, and the filtrate was concentrated. Thus obtained crude productwas separated and purified by means of column chromatography to giveGD08 (0.6 g, 0.93 mM, 35%).

[α]_(D) ²³ 58.5(c1.02,CHCl₃).

IR(CHCl₃) 2982, 2936, 1595, 1462, 1435, 1389, 1344, 1331, 1308, 1271,1234, 1211, 1198, 1144, 1034, 991, 928, 856 cm⁻¹.

Rf=0.3(Hexane:Ethyl acetate=5:1)

¹H NMR(400 MHz,CDCl₃) δ=7.48(s,2H), 4.95(dd,2H,J=1.3,6.2 Hz),4.87(dd,2H,J=1.3,6.2 Hz), 2.83-2.74(m,4H), 2.70(s,6H), 2.53-2.45(m,2H),2.18-2.11(m,2H), 1.72-1.60(m,8H), 1.32(s,24H).

¹³C NMR(100 MHz,CDCl₃) δ=158.42, 141.46, 136.74, 132.35, 131.32, 100.46,83.37, 55.76, 29.47, 28.03, 24.89, 24.69, 23.07, 22.98.

Anal. Calcd for: C,68.15; H,8.26; found: C,68.28; H,8.05.

From GD08,(R)-2,2′-Dihydroxy-3,3′-bis(4-nitrophenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-dinaphthyl(GD09, formula (28) below, 1.0 g, 1.91 mM, 97%) was synthesized.

[α]_(D) ²⁵−170.1(c1.06,CHCl₃).

IR(CHCl₃) 3520, 3028, 2939, 2862, 1597, 1518, 1462, 1437, 1394, 1346,1325, 1290, 1234, 1178, 1134, 1109, 856 cm⁻¹.

Rf=0.3(Hexane:Ethyl acetate=8:1)

¹H NMR(400 MHz,CDCl₃) δ=8.29-8.26(m,4H), 7.81-7.79(m,4H), 7.23(s,2H),4.92(s,2H), 2.83-2.82(m,4H), 2.42-2.36(m,2H), 2.30-2.24(m,2H),1.80-1.76(m,8H).

¹³C NMR(100 MHz,CDCl₃) δ=148.21, 146.44, 144.57, 138.29, 132.03, 131.07,129.85, 123.89, 123.30, 119.37, 29.28, 27.39, 22.94, 22.92.

Anal. Calcd for: C,71.63; H,5.26; N,5.22; found: C,71.53;H,5.29; N,5.01.

Synthetic Example 58 Synthesis of(R)-3,3′-Bis(4-nitrophenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-dinaphthylphosphate (GD10)

GD09 was subjected to the same procedure as that in the method ofsynthesizing GC02 to synthesize GD10, from which the raw material wasremoved by means of column chromatography. The obtained solid wasdissolved in methanol, and was purified by the reprecipitation in 6 Nhydrochloric acid to give GD10 (formula (29) below, 0.4 g, 0.71 mM,53%).

[α]_(D) ²⁴−238.5(c1.00,CHCl₃).

IR(CHCl₃) 2943, 2843, 1603, 1518, 1435, 1391, 1263, 1217, 1194, 1109,1022, 955, 899, 854 cm⁻¹.

¹H NMR(400 MHz,CDCl₃) δ=8.09-8.08(m,4H), 7.64-7.58(m,4H), 7.21(s,2H),2.93-2.88(m,4H), 2.75-2.72(m,2H), 2.47-2.43(m,2H), 1.80-1.82(m,8H).

³¹P NMR(400 MHz,CDCl₃) δ=1.16.

¹³C NMR(100 MHz,CDCl₃) δ=146.70, 143.13, 142.21, 142.10, 139.33, 136.20,130.77, 130.05, 129.27, 126.79, 123.18, 29.34, 28.02, 22.55, 22.40.

Anal. Calcd for: C,64.21; H,4.55; N,4.68; found: C,64.49; H,4.76;N,4.71.

Synthetic Example 59 Synthesis of(R)-3,3′-Bis(4-trifluoromethylphenyl)-2,2′-dihydroxy-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-dinaphthyl(GD11)

The procedure of GD05 was repeated to give GD11 (0.9 g, 1.60 mM, 80%).

[α]_(D) ²⁵−39.7(c1.03,CHCl₃).

IR(CHCl₃) 3522, 2937, 2862, 1618, 1464, 1439, 1396, 1325, 1292, 1236,1169, 1132, 1111, 1069, 1020, 845 cm⁻¹.

¹H NMR(400 MHz,CDCl₃) δ=7.73(d,4H,J=8.2 Hz), 7.67(d,4H,J=8.2 Hz),7.19(s,2H), 4.88(s,2H), 2.83-2.80(m,4H), 2.43-2.35(m,2H),2.29-2.22(m,2H), 1.79-1.73(m,8H).

¹³C NMR(100 MHz,CDCl₃) δ=148.25, 141.56, 137.57, 132.05, 130.83, 129.52,129.18, 128.87, 125.66, 125.15, 125.11, 124.81, 122.96, 119.63, 29.21,27.22, 22.92, 22.90.

¹⁹F NMR(376 MHz,CDCl₃) δ=99.30(s).

Anal. Calcd for: C,70.10; H,4.84; found: C,70.36; H,4.89.

Synthetic Example 60 Synthesis of(R)-3,3′-Bis(4-trifluoromethylphenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-dinaphthylphosphate (GD12)

GD11 was subjected to the same procedure as that in method ofsynthesizing GC02 to synthesize GD12, and then the starting material wasseparated by means of column chromatography. The obtained solid wasdissolved in methanol, and was purified by the reprecipitation in 6 Nhydrochloric acid to give GD12 (formula (30) below, 0.5 g, 0.80 mM,66%).

[α]_(D) ²⁵−171.5(c1.02,CHCl₃).

IR(CHCl₃) 2941, 2864, 1620, 1435, 1393, 1325, 1259, 1192, 1167, 1128,1069, 1022, 957, 901, 845 cm⁻¹.

¹H NMR(400 MHz,CDCl₃) δ=7.54-7.46(m,8H), 7.13(s,2H), 2.87-2.86(m,4H),2.67-2.64(m,2H), 2.39-2.34(m,2H), 1.85-1.80(m,6H), 1.68-1.60(m,2H).

³¹P NMR(400 MHz,CDCl₃) δ=2.30.

¹³C NMR(100 MHz,CDCl₃) δ=142.55, 140.43, 138.55, 135.89, 131.17, 130.26,129.65, 129.34, 129.03, 126.79, 125.60, 124.98, 124.95, 122.89, 29.19,27.83, 22.50, 22.34.

¹⁹F NMR(376 MHz,CDCl₃) δ=99.20(s).

Anal. Calcd for: C,63.36; H,4.22; found: C,63.61; H,4.09.

Example 1 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA04

MI01 (0.15 mmol), GA04 (0.045 mmol) and Ethylbenzene (1 mL) were put ina two-necked round bottom flask and stirred at −80° C. MK01 (0.45 mmol)was added dropwise, and the reaction mixture was stirred at −80° C. for30.5 hours (Entry 1 in Table 1 below). Entries 2-11 in Table 1 were alsosubjected to the similar procedure under the conditions shown in Table1.

After that, the reaction was quenched by the addition of a saturatedaqueous sodium hydrogen carbonate solution, and the mixture was warmedto room temperature. The reaction mixture was filtered over celite, andextracted with ethyl acetate three times. The ethyl acetate layer waswashed with a saturated aqueous sodium chloride solution, and dehydratedover anhydrous sodium sulfate. After the dehydration, the extract wasfiltered. The concentrated filtrate was purified by means of preparativeTLC (Hexane:AcOEt=3:1) to give Methyl3-N-(2-hydroxyphenyl)amino-2,2-dimethyl-3-phenylpropionate (P01)represented by formula (31) below.

Here, in the case of Entries 4 and 5 in Table 1, 0.015 mmol of GA04 and0.09 mmol of GA04 were used, respectively, relative to MI01 (0.15 mmol).

For each P01 obtained in respective Entries, Optical Purity (% ee) wasdetermined by HPLC analysis. These results are shown in Table 1.

Instrumental Analysis Data etc. of P01

Rf=0.4(Hexane:AcOEt=3:1, developed twice).

¹H-NMR(400 MHz,CDCl₃) δ=7.29-7.19(m,5H), 6.69-6.49(m,3H),6.39-6.37(m,1H), 5.80(brs,1H), 4.93(brs,1H), 4.57(s,1H), 3.68(s,3H),1.24(s,3H), 1.21(s,3H).

¹³C-NMR(100 MHz,CDCl₃) δ=177.72, 144.26, 138.97, 135.54, 128.34, 127.92,127.41, 121.02, 117.92, 114.25, 113.91, 64.58, 52.23, 47.35, 24.36,20.01.

HPLC: tR=12.6 min., tR=19.8 min.

-   -   Daicel Chiralpack AD-H    -   Hexane/i-Propanol=5/1    -   UV=244 nm

Flow rate=0.5 ml/min.

TABLE 1 Temperature Entry Solvent ° C. Time hr Yield % % ee 1Ethylbenzene −80 30.5 quant 31 2 Toluene −80 20 quant 27 3 Toluene −8044.5 94 24 4 Toluene −80 46 68 27 5 Toluene −80 26 quant 29 6 Toluene 046.5 13 15 7 o-Xylene −20 46 58 26 8 Mesitylene −40 47 86 39 9 Hexane−80 20 20 4 10 Diethyl ether −80 48 34 6 11 Ethanol −80 17.5 quant 2

Example 2 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA11

The procedure of Example 1 was repeated except that GA04 was changed toGA11. The result is shown in Table 2. TABLE 2 Entry Solvent Temperature° C. Time hr Yield % % ee 1 Mesitylene −40 48 4 9 2 CH₂Cl₂ −80 37.5 19 1

Example 3 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA15

The procedure of Example 1 was repeated except that GA04 was changed toGA15. The result is shown in Table 3. TABLE 3 Temperature Entry Solvent° C. Time hr Yield % % ee 1 THF −80 41 51 46 2 Et₂O −80 27 30 46 3i-Propylbenzene −80 34.5 29 54 4 Ethylbenzene −80 34.5 91 58 5 Toluene−80 26.5 quant 60 6 Toluene −80 40.5 70 52 7 Mesitylene −40 10 95 19 8Mesitylene + MS −40 45 57 62 4A 9 CH₂Cl₂ −80 8.5 quant 8

Example 4 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA19

The procedure of Example 1 was repeated except that GA04 was changed toGA19. The result is shown in Table 4. TABLE 4 Temperature Entry Solvent° C. Time hr Yield % % ee 1 CH₂Cl₂ −78 3 quant 5 2 Diethyl ether −78 5121 2 3 Methanol −78 18.5 quant 2 4 i-Propylbenzene −78 43 40 28 5Ethylbenzene −78 39 91 46 6 Toluene −80 40.5 quant 56 7 m-Xylene −4046.5 40 10 8 Mesitylene −40 43 56 15

Example 5 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA29

The procedure of Example 1 was repeated except that GA04 was changed toGA29. The result is shown in Table 5. TABLE 5 Temperature Entry Solvent° C. Time hr Yield % % ee 1 Ethylbenzene −78 43.5 69 33 2 Toluene −80 5183 35 3 Mesitylene −40 26 96 29 4 Anisole −35 46 66 12

Example 6 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA38

The procedure of Example 1 was repeated except that GA04 was changed toGA38. The result is shown in Table 6. TABLE 6 Temperature Entry Solvent° C. Time hr Yield % % ee 1 Ethylbenzene −78 47 80 3 2 Toluene −78 59 812

Example 7 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGA04

MI01 (0.15 mmol), GA04 (0.045 mmol) and Ethylbenzene (1 mL) were put ina two-necked round bottom flask, was cooled to −40° C., and stirred.MK03 (0.474 mmol) was added dropwise, and the reaction mixture wasstirred at −40° C. for 17 hours. The mixture was stirred for additional11 hours at room temperature. Then, the reaction was quenched by theaddition of a saturated aqueous sodium hydrogen carbonate solution. Thereaction mixture was filtered over celite, and was then extracted withethyl acetate three times. The ethyl acetate layer was washed with asaturated aqueous sodium chloride solution and dehydrated over anhydroussodium sulfate. After the dehydration, the extract was filtered. Theconcentrated filtrate was purified by means of preparative TLC(Hexane:AcOEt=3:1) to give i-Propyl3-N-(2-hydroxyphenyl)amino-2,2-dimethyl-3-phenylpropionate (P03).

The yield was 8%. The Optical Purity was 33% ee.

Rf=0.3(Hexane:AcOEt=2:1)

¹H-NMR(400 MHz,CDCl₃) δ=7.31-7.20(m,5H), 6.68-6.66(d,1H,J=7.7 Hz),6.63-6.59(t,1H,J=7.7 Hz), 6.54-6.50(d,1H,J=7.7 Hz), 6.39-6.37(m,1H,J=7.7Hz), 5.19(brs,1H), 5.06-5.89(qq,1H,J=7.1,6.2 Hz), 4.91(brs,1H),4.53(s,1H), 1.24-1.22(d,3H,J=7.1 Hz), 1.22(s,3H), 1.17(s,3H),1.16-1.15(d,3H,J=6.2 Hz).

HPLC: tR=12.3 min., tR=18.0 min.

-   -   Daicel Chiralpack AD-H    -   Hexane/i-PrOH=9/1    -   UV=244 nm    -   Flow rate=0.5 ml/min.

Example 8 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGB15

MI01 (0.15 mmol), GB15 (0.045 mmol) and i-Propylbenzene (1 mL) were putin a two-necked round bottom flask and stirred at −78° C. MK01 (0.471mmol) was added dropwise, and the reaction mixture was stirred at −78°C. for 48 hours (Entry 1 in Table 7 below). Entries 2-4 in Table 7 werealso subjected to the similar procedure under the conditions shown inTable 7.

After that, the reaction was quenched by the addition of a saturatedaqueous sodium hydrogen carbonate solution, and the mixture was warmedto room temperature. The reaction mixture was filtered over celite, andextracted with ethyl acetate three times. The ethyl acetate layer waswashed with a saturated aqueous sodium chloride solution, and dehydratedover anhydrous sodium sulfate. After the dehydration, the extract wasfiltered. The concentrated filtrate was purified by means of preparativeTLC (Hexane:AcOEt=3:1) to give P01.

For each P01 obtained in respective Entries, Optical Purity (% ee) wasdetermined by HPLC analysis. These results are shown in Table 7. TABLE 7Temperature Entry Solvent ° C. Time hr Yield % % ee 1 i-Propylbenzene−78 48 34 35 2 Toluene −80 48 36 32 3 Mesitylene −40 31 54 13 4Ethylbenzene −80 48 31 31

Example 9 Asymmetric Synthesis by using a Chiral Broensted Acid CatalystGC02

MI01 (0.15 mmol), GC02 (0.045 mmol) and Toluene (1 mL) were put in atwo-necked round bottom flask and stirred at −78° C. MK01 (0.45 mmol)was added dropwise, and the reaction mixture was stirred at −78° C. for4 hours (disappearance of MI01 was checked by means of TLC, Entry 1 inTable 8). Entries 2-7 were also subjected to the same procedure underthe conditions shown in Table 8.

After that, the reaction was quenched by the addition of a saturatedaqueous sodium hydrogen carbonate solution, and the mixture was warmedto room temperature. The reaction mixture was filtered over celite andextracted with ethyl acetate three times. The ethyl acetate layer waswashed with 1 M hydrochloric acid and a saturated aqueous sodiumchloride solution, and dehydrated over anhydrous sodium sulfate. Afterthe dehydration, the extract was filtered. The concentrated filtrate waspurified by means of preparative TLC (Hexane:AcOEt=3:1) to give Methyl3-N-(2-hydroxyphenyl)amino-2,2-dimethyl-3-phenylpropionate (P01).

For each P01 obtained in respective Entries, Optical Purity (% ee) wasdetermined by HPLC analysis. These results are shown in Table 8. TABLE 8Temperature Entry Solvent ° C. Time hr Yield % % ee 1 Toluene −78 4 9687 2 Ethylbenzene −78 4.5 100 83 3 Mesitylene −78 1 100 77 4Diethylether −78 26 98 30 5 CH₂Cl₂ −78 1 100 13 6 Toluene −40 4 100 81 7Toluene 0 4 67 73

Example 10 Asymmetric Synthesis by using a Chiral Broensted AcidCatalyst GC02

The procedure of Example 9 was repeated except that the ratio of GC02 toMI01 was changed (in this connection, the condition for Entry 1 was thesame as that for Entry 1 in Example 9). The results are shown in Table9. TABLE 9 Entry Solvent MI01 (mmol) GC02 (mmol) Time Yield % ee 1Toluene 0.15 0.045 4 hr 96% 87 2 Toluene 0.15 0.015 7 hr 100% 89 3Toluene 0.15 0.0075 20 hr  100% 83

Example 11 Asymmetric Synthesis by using a Chiral Broensted AcidCatalyst GC06

The procedure of Example 9 was repeated except that GA02 was changed toGA06. The used solvents, reaction temperatures, and results (% ee) areshown in Table 10. TABLE 10 Temperature Entry Solvent ° C. Time hr Yield% % ee 1 Toluene −78 46.5 58 45 2 Ethylbenzene −78 44.5 61 45 3Mesitylene −40 23 99 62

Example 12 Asymmetric Synthesis by using GC08, GC09 or GB15

MI01 (0.16 mM), GC08 (0.016 mM) as a chiral Broensted acid catalyst, andtoluene (1 mL) were put, in this order, in a dried two-necked roundbottom flask (10 mL) under nitrogen atmosphere and stirred at −78° C.for 10 minutes. MK01 (0.24 mM) was added dropwise over 3 minutes. Afterchecking disappearance of MI01 by means of TLC, a saturated aqueoussodium hydrogen carbonate solution and a saturated aqueous potassiumfluoride solution were added dropwise over 3 minutes, and the mixturewas stirred until it was warmed to room temperature to quench thereaction. The reaction mixture was filtered over celite, and extractedwith ethyl acetate three times. The combined ethyl acetate extracts waswashed sequentially with 1N hydrochloric acid and brine, and dried overanhydrous sodium sulfate. After the drying, the extract was filtered.The concentrated filtrate was separated and purified by means of p-TLCto give a Mannich adduct (P01). Optical purity thereof was determined bymeans of high-performance mixture chromatography.

GC09 or GB15 was also used for conducting similar asymmetric synthesis.These results are listed in Table 11. TABLE 11 Chiral Reaction Broenstedacid time hr Yield % % ee GC08 17 79 47 GC09 2 quant. 66 GC11 42  6 7GB15 45.5 99 52

Example 13 Asymmetric Synthesis by using GD02, GD06, GD10 or GD12

The asymmetric synthesis procedure of Example 12 was repeated exceptthat GA08 was changed to GA02. Also, GD06, GD10 or GD12 was used forconducting similar asymmetric synthesis. These results are shown inTable 12. TABLE 12 Chiral Reaction Broensted acid time hr Yield % % eeGD02 22.5 quant. 16 GD06 46 83 48 GD10 44 quant. 81 GD12 46.5 84 68

Example 14 Asymmetric Synthesis by using GC02: Investigation of ImineCompounds

A Mannich adduct was asymmetrically synthesized from one of iminecompounds (formula (32) below) shown in Table 13 and MK01 using GC02 asa catalyst. The result is shown in Table 13. Here, conditions for theasymmetric synthesis were the same as those shown in Example 12. TABLE13 Imine compound Reaction time Synthesized Entry R = hr Yield % % eecompound 1 Ph 13 98 89 4aa 2 4-FC₆H₄ 10 quant. 85 4ga 3 4-ClC₆H₄ 24quant. 80 4ha 4 4-BrC₆H₄ 35 quant. 76 4ia 5 4-NO₂C₆H₄ 46 40 78 4ja 61-naphthyl 31 92 39 4ka 7 2-MeC₆H₄ 42 84 51 4la 8 4-MeC₆H₄ 35 quant. 894ma 9 4-MeOC₆H₄ 46.5 86 75 4na 10 2-Furyl 5 88 75 4oa 11 2-Thienyl 48 7269 4pa 12 PHCH═CH 34 98 80 4qa

Compound of Entry 1 (4aa)

[α]_(D) ²⁵ 0.2(c1.03,CHCl₃).

Rf=0.4(Hexane:Ethyl acetate=3:1)

¹H NMR(400 MHz,CDCl₃) δ=7.29-7.19(m,5H), 6.69-6.49(m,3H),6.39-6.37(m,1H), 5.80(brs,1H), 4.93(brs,1H), 4.57(s,1H), 3.68(s,3H),1.24(s,3H), 1.21(s,3H).

¹³C NMR(100 MHz,CDCl₃) δ=177.7, 144.3, 139.0, 135.5, 128.3, 127.9,127.4, 121.0, 117.9, 114.3, 113.9, 64.6, 52.2, 47.4, 24.4, 20.0.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=11.1 min(3R), tR=16.0 min(3S).

Hereinafter, respective structures of compounds of Entries 2-12 weredetermined in the same way.

Compound of Entry 2 (4ga)

[α]_(D) ²⁴−15.4(c1.06,CHCl₃).

¹⁹F NMR(400 MHz,CDCl₃)δ=−46.52.

MS m/z 317(M⁺), 217, 216, 215, 214, 120, 109.

Anal. Calcd for: C,68.12; H,6.35; N,4.41; found: C,68.04; H,6.50;N,4.40.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=10.5 min(3R), tR=14.9 min(3S).        Compound of Entry 3 (4ha)

[α]_(D) ²⁵−7.8(c0.99,CHCl₃).

Rf=0.3(Hexane:Ethyl acetate=3:1)

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=10.2 min(3R), tR=15.7 min(3S).        Compound of Entry 4 (4ia)

[α]_(D) ²⁰ 9.0(c1.15,CHCl₃). oil.

Rf=0.4(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,57.15; H,5.33; N,3.70; found: C,57.37; H,5.08;N,3.32.

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=18.6 min(3S), tR=22.0 min(3R).        Compound of Entry 5 (4ja)

[α]_(D) ²⁴ 22.9(c0.53,CHCl₃). amorphous.

Rf=0.2(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,62.78; H,5.85; N,8.13; found: C,62.75; H,5.97;N,7.97.

HPLC: Daicel Chiralpak OD-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=38.2 min(3S), tR=42.3 min(3R).        Compound of Entry 6 (4ka)

[α]_(D) ²⁵−90.5(c1.07,CHCl₃).

Rf=0.3(Hexane:Ethyl acetate=3:1)

HPLC: Daicel Chiralpak OD-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=18.6 min(3S), tR=22.0 min(3R).        Compound of Entry 7 (4la)

Rf=0.3(Hexane:Ethyl acetate=3:1)

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=11.5 min(3R), tR=18.8 min(3S).        Compound of Entry 8 (4ma)

[α]_(D) ²⁴ 16.2(c0.99,CHCl₃). oil.

Anal. Calcd for: C,72.82; H,7.40; N,4.47; found: C,72.98; H,7.54;N,4.53.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate 0.6 ml/min,UV=244 nm,

-   -   tR=8.3 min(3R), tR=13.6 min(3S).        Compound of Entry 9 (4na)

[α]_(D) ²⁴ 8.9(c0.99,CHCl₃). oil.

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,69.28; H,7.04; N,4.25; found: C,69.42; H,6.92;N,4.23.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.7 ml/min,UV=244 nm,

-   -   tR=8.9 min(3R), tR=16.8 min(3S).        Compound of Entry 10 (4oa)

[α]_(D) ²⁴−52.2(c0.92,CHCl₃). amorphous.

Rf=0.4(Hexane:Ethyl acetate=5:1)

Anal. Calcd for: C,66.42; H,6.62; N,4.84; found: C,66.66; H,6.52;N,4.91.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=22.9 min(3R), tR=26.7 min(3S).        Compound of Entry 11 (4pa)

[α]_(D) ²⁴−12.5(c1.06,CHCl₃). amorphous.

Rf=0.4(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,62.93; H,6.27; N,4.59; S,10.50; found: C,62.96;H,6.39; N,4.51; S,10.66.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=10/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=20.1 min(3R), tR=23.9 min(3S).        Compound of Entry 12 (4qa)

[α]_(D) ²⁰ 102.1(c0.95,CHCl₃). amorphous.

Anal. Calcd for: C,73.82; H,7.12; N,4.30; found: C,73.95; H,7.27;N,4.09.

HPLC: Daicel Chiralpak AS-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=20.7 min(3S), tR=24.6 min(3R).

Example 15 Investigation of Nucleophilic Agents in Asymmetric MannichReactions

One of nucleophilic agents (formula (33) below) shown in Table 14 andMI01 were used to conduct asymmetric synthesis of a Mannich adduct,using GC02 as a catalyst. The result is shown in Table 14. Here,conditions for the asymmetric synthesis were the same as those shown inExample 12. TABLE 14 Reaction Reac- Syn- tem- tion % thesized R₁ R₂ R₃R₄ perature time Yield % ee compound 1 Me Me TMS OMe −78° C. 13 98 894aa 2 Me Me TMS OEt −78° C. 23 quant. 79 4ab 3 Me Me TMS OiPr −78° C. 3026 39 4ac 4 Me Me TBS OMe −78° C. 23 45 76 4aa 5 H H TBS OMe −40° C.22.5 29 62 4ae 6 H H TMS SEt −78° C. 46 97 45 4ag

Compound of Entry 5 (4ae)

Rf=0.2(Hexane:Ethyl acetate=3:1)

HPLC: Daicel Chiralpak AS-H, Hexane/i-PrOH=10/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=39.6 min(3R), tR=44.1 min(3S).        Compound of Entry 6 (4ag)

Rf=0.3(Hexane:Ethyl acetate=5:1)

HPLC: Daicel Chiralpak AS-H, Hexane/i-PrOH=9/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=23.4 min(3R), tR=29.7 min(3S).

Example 16 Investigation of Diastereo-Selective Mannich Reactions:Investigation of Nucleophilic Agents

One of nucleophilic agents (formula (34) below) shown in Table 15 andMI01 were used to conduct synthesis of respective diastereo-selectiveMannich adducts (formulae (35) and (36) below) using GC02 as a catalyst.The result is shown in Table 15. Here, conditions for the asymmetricsynthesis were the same as those shown in Example 12. As for thenucleophilic agent, one having E/Z=87/13 was used in Entry 1, one havingE/Z=91/9 was used in Entries 2 and 3, and one having E/Z=96/4 was usedin Entry 4. TABLE 15 Syn- Reation syn/ % ee thesized Entry R₅ R₆ timeYield % anti (syn/anti) compound 1 Me Et 17 quant.  87/13 96/— 4ai 2 BnEt 19 quant. 93/7 91/— 4aj 3 TPSO Me 6 79 100/0  91/— 4ak 4 TBSO Me 1 9694/6 85/59 4al

Compound of Entry 1 (4ai, syn/anti=87/13)

Rf=0.2(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,72.22; H,7.02; N,4.68; found: C,72.37; H,7.29;N,4.56.

HPLC: Daicel Chiralpak AS-H, Hexane/i-PrOH=30/1, Flow rate=0.55 ml/min,UV=244 nm,

-   -   tR=48.3 min(2S,3R), tR=56.7 min(2R,3S).        Compound of Entry 2 (4aj, syn/anti=93/7)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,76.77; H,6.71; N,3.73. found:C,76.54; H,6.64; N,3.79.

HPLC: Daicel Chiralpak AS-H, Hexane/i-PrOH=30/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=54.9 min(2S,3R), tR=64.4 min(2R,3S).        Compound of Entry 3 (4ak, syn/anti=100/0)

[α]_(D) ²⁵ 27.8(c1.03,CHCl₃)(91% ee).

amorphous.

Anal. Calcd for: C,74.83; H,5.73; N,2.57; found: C,74.54; H,5.61;N,2.37.

HPLC: Daicel Chiralpak AS-H, Hexane/EtOH=50/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=37.8 min(2S,3R), tR=42.9 min(2R,3S).        Compound of Entry 4 (4al, syn/anti=94/6)

Rf=0.4(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,65.80; H,7.78; N,3.49; found: C,65.96; H,7.49;N,3.34.

HPLC: Daicel Chiralpak AD-H, Hexane/EtOH=25/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=11.1 min(2S,3R), tR=17.4 min(2R,3S).

Example 17 Investigation of Diastereo-Selective Mannich Reactions:Investigation of Imine Compounds

One of imine compounds (formula (32) above) shown in Table 16 and one ofnucleophilic agents (formula (37) below) were used to conduct synthesisof respective diastereo-selective Mannich adducts (formula (38) andformula (39) below) using GC02 as a catalyst. The result is shown inTable 16. Here, conditions for the asymmetric synthesis were the same asthose shown in Example 12. As for the nucleophilic agent, one havingE/Z=87/13 was used in Entries 1-7, one having E/Z=87/13 was used inEntries 8-11, one having E/Z=91/9 was used in Entry 12, and one havingE/Z=96/4 was used in Entries 13-14. TABLE 16 Reaction syn/ % eeSynthesized Entry R R₅ R₆ time Yield % anti (syn/anti) compound 1 Ph MeEt 17 quant.  87/13 96/— 4ai 2 4-FC₆H₄ Me Et 3.5 quant. 91/9 84/36 4gi 34-ClC₆H₄ Me Et 7 quant.  86/14 83/14 4hi 4 4-MeC₆H₄ Me Et 22 quant. 94/681/35 4mi 5 4-MeOC₆H₄ Me Et 24 quant. 92/8 88/38 4ni 6 2-Thienyl Me Et41 85 94/6 88/3  4pi 7 PhCH═CH Me Et 37 91 95/5 90/49 4qi 8 Ph Bn Et 19quant. 93/7 91/— 4aj 9 4-MeOC₆H₄ Bn Et 43.5 92 93/7 87/23 4nj 10 4-FC₆H₄Bn Et 10 98  87/13 81/20 4gi 11 PhCH═CH Bn Et 46.5 65 95/5 90/15 4qi 12Ph TPSO Me 6 79 100/0  91/— 4ak 13 4-MeOC₆H₄ TPSO Me 46 98 100/0  84/—4nk 14 PhCH═CH TPSO Me 46 86 100/0  91/— 4qk

Compound of Entry 2 (4gi, syn/anti=91/9)

Rf=0.3(Hexane:Ethyl acetate=3:1)

¹⁹F NMR(376 MHz,CDCl₃) δ=46.74(s,anti),46.29(s,syn).

Anal. Calcd for: C,68.12; H,6.35; N,4.41; found: C,67.90; H,6.35;N,4.31.

HPLC: Daicel Chiralcel OJ-H, Hexane/i-PrOH=9/1, Flow rate=0.7 ml/min,UV=244 nm,

-   -   tR=43.2 min(2S,3R), tR=56.2 min(2R,3S).        Compound of Entry 3 (4hi, syn/anti=86/14)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,64.77; H,6.04; N,4.20; found: C,64.56; H,5.81;N,4.19.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=30/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=62.4 min(2S,3R), tR=73.8 min(2R,3S).        Compound of Entry 4 (4mi, syn/anti=94/6)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,72.82; H,7.40; N,4.47; found: C,72.75; H,7.75;N,4.35.

HPLC: Daicel Chiralpak AD-H, Hexane/EtOH=40/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=46.4 min(2S,3R), tR=56.2 min(2R,3S).        Compound of Entry 5 (4ni, syn/anti=92/8)

Rf=0.2(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,69.28; H,7.04; N,4.25; found: C,69.11; H,6.73;N,4.09.

HPLC: Daicel Chiralcel OJ-H, Hexane/EtOH=5/1, Flow rate=0.8 ml/min,UV=244 nm,

-   -   tR=22.4 min(2S,3R), tR=29.8 min(2R,3S).        Compound of Entry 6 (4pi, syn/anti=94/6)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,62.93; H,6.27; N,4.59; S,10.50; found: C,62.55;H,6.49; N,4.25; S,10.39.

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=40/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=69.7 min(2S,3R), tR=80.7 min(2R,3S).        Compound of Entry 7 (4qi, syn/anti=95/5)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,73.82; H,7.12; N,4.30; found: C,73.43; H,6.97;N,4.15.

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=15/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=29.3 min(2S,3R), tR=33.5 min(2R,3S).        Compound of Entry 9 (4nj, syn/anti=93/7)

Rf=0.3(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,74.05; H,6.71; N,3.45; found: C,74.22; H,6.87;N,3.25.

HPLC: Daicel Chiralpak AD-H, Hexane/i-PrOH=5/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=21.7 min(2S,3R), tR=34.7 min(2R,3S).        Compound of Entry 10 (4gj, syn/anti=87/13)

Rf=0.2(Hexane:Ethyl acetate=5:1)

Anal. Calcd for: C,73.26; H,6.15; N,3.56; found: C,73.31; H,6.52;N,3.30.

HPLC: Daicel Chiralpak AD-H, Hexane/EtOH=10/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=23.4 min(2S,3R), tR=27.0 min(2R,3S).        Compound of Entry 11 (4qj, syn/anti=95/5)

Rf=0.4(Hexane:Ethyl acetate=3:1)

Anal. Calcd for: C,77.78; H,6.78; N,3.49; found: C,77.66; H,6.56;N,3.19.

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=30/1, Flow rate=1.0 mil/min,UV=244 nm,

-   -   tR=30.6 min(2S,3R), tR=58.2 min(2R,3S).        Compound of Entry 13 (4nk, syn/anti=100/0)

[α]_(D) ²⁵ 12.1(c0.91,CHCl₃,84% ee). oil.

Rf=0.2(Hexane:Ethyl acetate=5:1)

Anal. Calcd for: C,73.02; H,5.78; N,2.43; found: C,73.29; H,5.76;N,2.33.

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=20/1, Flow rate=0.5 ml/min,UV=244 nm,

-   -   tR=20.8 min(2R,3S), tR=23.7 min(2S,3R).

Example 18 Asymmetric Hydrophosphorylation Reaction

0.118 mM of one of imine compounds represented by formula (40) below (agroup for Ar is shown in Table 17, for example,N-2-nitrobenzylidene4-methoxyaniline was used in Entry 1), GC11 (0.035mM) as a chiral Broensted acid catalyst, and toluene (1 mL) were put ina dried two-necked round bottom flask (10 mL) under nitrogen atmosphereand stirred at room temperature for 10 minutes. After that,diisopropylphosphite (0.173 mM) was added dropwise, and the reactionmixture was stirred for 24 hours. The reaction was quenched by theaddition of a saturated aqueous sodium hydrogen carbonate solution. Thereaction mixture was extracted with ethyl acetate three times. Theextract was washed with a saturated salt solution, and dried overanhydrous sodium sulfate. After the drying, the extract was filtered.The filtrate was concentrated under a reduced pressure, which wasseparated and purified by means of p-TLC (n-hexane:ethyl acetate) togive the compound represented by formula (41) (Entry 1: n-hexane:ethylacetate=1:1, Rf=0.3; 35.6 mg, 0.085 mM, yield: 72%, 77% ee). Opticalpurity thereof was determined by means of high-performance mixturechromatography. These results are shown in Table 17.

TABLE 17 Imine compound Reaction Synthesized Entry Ar = time hr Yield %% ee compound 1 2-NO₂C₆H₄ 24 72 77 PP01 2 4-FC₆H₄ 24 80 50 PP02 3 Ph 2490 56 PP03 4 1-Furyl—CH═CH 24 44 70 PP04 5 1-Furyl 24 79 61 PP05 62-MeC₆H₄ 24 78 69 PP06 7 2-MeOC₆H₄ 24 <97 60 PP07 8 C₆H₅—CH═CH 24 49 80PP08 9 4-MeC₆H₄ 24 69 51 PP09Compound of Entry 1 (PP01)

¹H NMR(400 MHz,CDCl₃) δ=7.98(d,1H,J=7.50 Hz), 7.71(d,1H,J=4.94 Hz),7.54(t,1H,J=7.0 Hz), 7.40(d,1H,J=8.24 Hz), 6.73(d,2H,J=8.78 Hz),6.62(d,2H,J=8.60 Hz), 6.05(dd,1H,J=8.78,17.39 Hz),4.70-4.75(m,2H),4.52-4.57(m,1H), 3.69(s,3H), 1.31 (d,3H,J=6.22 Hz),1.27(d,3H,J=6.22 Hz), 1.22(d,3H,J=6.04 Hz), 0.90(d,3H,J=6.22 Hz).

HPLC: Daicel Chiralcel OD-H, Hexane/i-PrOH=60/1, Flow rate=0.3 ml/min,UV=254 nm,

-   -   tR=47.8 min(major), tR=52.2 min(minor).        Compound of Entry 2 (PP02)

¹H NMR(400 MHz,CDCl₃) δ=7.40-7.44(m,2H), 7.00(t,2H,J=8.60 Hz),6.69(d,J=8.78 Hz), 6.51(d,J=8.78 Hz), 4.46-4.71 (m,4H), 3.68(s,3H),1.31(d,3H,J=6.22 Hz), 1.27(d,3H,J=6.04 Hz), 1.22(d,3H,J=6.22 Hz),0.98(d,3H,J=6.22 Hz).

Compound of Entry 3 (PP03)

¹H NMR(400 MHz,CDCl₃) δ=7.43-7.46(m,2H), 7.30(t,2H,J=7.64 Hz),7.24(t,1H,J=2.01,5.67 Hz), 6.78(dt,2H,J=2.38,4.39 Hz),6.53(dt,2H,J=2.38,4.39 Hz),4.43-4.71(m,4H), 3.68(s,3H), 1.31(d,2H,J=6.22Hz), 1.25(d,2H,J=6.04 Hz), 1.22(d,2H,J=6.22 Hz), 0.92(d,2H,J=6.22 Hz).

Compound of Entry 4 (PP04)

¹H NMR(400 MHz,CDCl₃) δ=7.31(s,1H), 6.75(d,2H,J=8.78 Hz),6.62(d,2H,J=8.78 Hz), 6.49(dd,1H,J=5.03,10.98 Hz), 6.34(s,1H),6.18-6.25(m,2H), 4.70-4.76(m,2H), 4.26(dt,J=6.96,13.18 Hz),4.01(t,J=8.42 Hz), 3.74(s,3H), 1.33-1.35(m,6H), 1.28(d,3H,J=6.04 Hz),1.25(d,3H,J=6.22 Hz).

Compound of Entry 5 (PP05)

¹H NMR(400 MHz,CDCl₃) δ=7.36(d,1H,J=0.73 Hz), 6.73(d,2H,J=2.20 Hz),6.72(d,2H,J=2.38 Hz), 6.34(t,2H,J=3.11,3.29 Hz), 4.68-6.80(m,2H),4.55-4.60(dd,1H,J=6.22,7.14 Hz), 4.26(t,1H,J=7.14 Hz), 3.71(s,3H),1.34(d,3H,J=6.22 Hz), 1.30(d,3H,J=6.22 Hz), 1.27(d,3H,J=6.22 Hz),1.07(d,3H,J=6.04 Hz).

Compound of Entry 6 (PP06)

¹H NMR(400 MHz,CDCl₃) δ=7.47(d,1H,J=2.38 Hz), 7.09-7.15(m,3H),6.65-6.81(m,2H), 6.45-6.49(m,2H), 4.84(dd,1H,J=7.32,16.84 Hz),4.68-4.75(m,1H), 4.59(t,1H,J=8.24,7.87 Hz), 4.34-4.41(m,1H), 3.67(s,3H),2.49(s,3H), 1.32(d,3H,J=6.04 Hz), 1.26(dd,6H,J=6.22,3.66 Hz),0.79(d,3H,J=6.22 Hz).

Compound of Entry 7 (PP07)

¹H NMR(400 MHz,CDCl₃) δ=7.44(dt,1H,J=2.47,1.50,3.66 Hz),7.20(t,1H,J=8.24,5.49 Hz), 6.90(t,1H,J=7.60 Hz), 6.87(d,1H,J=8.42 Hz),6.66(d,2H,J=6.59 Hz), 6.56(d,2H,J=6.77 Hz), 5.25(dd,1H,J=9.52,9.15 Hz),4.75-4.80(m,1H), 4.75(t,1H,J=8.97 Hz), 4.35-4.40(m,1H), 3.90(s,3H),3.67(s,3H), 1.32(d,3H,J=6.22 Hz), 1.27(d,3H,J=6.22 Hz), 1.20(d,3H,J=6.22Hz), 0.80(d,3H,J=6.22 Hz).

Compound of Entry 8 (PP08)

¹H NMR(400 MHz,CDCl₃) δ=7.33(d,2H,J=7.69 Hz), 7.28(d,2H,J=7.69 Hz),7.20(dd,1H,J=7.32,6.77 Hz), 6.73(d,2H,J=8.97 Hz), 6.63(d,2H,J=8.78 Hz),6.25(dd,1H,J=4.94,6.04,5.12 Hz), 4.71-4.79(m,1H),4.29(ddd,1H,J=6.8,8.8,12.4 Hz), 4.01(dd,1H,J=8.60,8.05 Hz), 3.73(s,3H),1.34(d,6H,J=6.22 Hz), 1.22-1.27(m,6H).

Compound of Entry 9 (PP09)

¹H NMR(400 MHz,CDCl₃) δ=7.32(dd,2H,J=2.19,6.04 Hz), 7.10(d,2H,J=8.05Hz), 6.67(dd,2H,J=2.19,4.39 Hz), 6.53(dd,2H,J=2.19,4.57 Hz), 6.89(m,1H),4.44-4.61(m,3H), 3.07(s,3H), 2.30(s,3H), 1.31(d,3H,J=6.22 Hz),1.26(d,3H,J=6.04 Hz), 1.23(d,3H,J=6.22 Hz), 0.95(d,3H,J=6.22 Hz).

Example 19 Asymmetric aza Diels-Alder Reaction: Investigation of Solvent

MI01 (0.15 mM), GC11 (0.1 eq.) and one of solvents shown in Table 18(1.0 mL) were put in a dried two-necked round bottom flask (10 mL) undernitrogen atmosphere and stirred at −78° C. for 10 minutes.1-Methoxy-3-trimetylsiloxy-1,3-butadiene (Danishefsky'diene, 0.3 mM) wasadded dropwise over 2 minutes. After checking decrease in color of MI01(detected with 2,4-dinitrophenylhydrazine) by means of TLC, a saturatedaqueous sodium hydrogen carbonate solution and a saturated aqueouspotassium fluoride solution was added dropwise thereto in this order.Then, the mixture was stirred for additional 30 minutes at roomtemperature. After that, the reaction mixture was filtered over celite.Then, the filtrate was extracted with dichloromethane three times. Theorganic layer was washed with 1 N hydrochloric acid and a saturated saltsolution followed by drying over anhydrous sodium sulfate. After thedrying, the crude liquid obtained by concentrating the filtrate waspurified by means of p-TLC to give1-(2-hydroxyphenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-4-one (PDA01).

The result obtained for each solvent is shown in Table 18.

Rf=0.3(silica gel, chloroform/isopropanol=19/1)

¹H NMR(400 MHz,CDCl₃) δ=9.50(brs,1H), 7.43(d,1H,J=7.6 Hz),7.26-6.66(m,9H), 5.30(dd,1H,J=6.7,7.1 Hz), 5.24(d,1H,J=7.6 Hz),3.25(dd,1H,J=7.1,17.0 Hz), 2.87(dd,1H,J=6.7,17.0 Hz).

HPLC: Daicel Chiralpack AD-H, n-hexane/ethanol=10/1, flow rate=0.5ml/min

-   -   tR=28.6 min(R), tR=33.8 min(S)

The absolute configuration of R-form and S-form was determined bycomparing with literature values after inducing PDA01 to1-(2-benzoloxyphenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-one.

1-(3-methoxyphenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-one

Rf=0.3(silica gel, n-hexane/ethyl acetate=1/2)

¹H NMR(400 MHz,CDCl₃) δ=7.68(dd,1H,J=7.9 Hz,1.1 Hz), 7.34-7.18(m,6H),6.66-6.54(m,3H), 5.29-5.26(m,2H), 3.73(s,3H), 3.30(dd,1H,J=16.4 Hz,7.1Hz), 2.78(ddd,1H,J=16.4 Hz,2.9 Hz,1.1 Hz).

HPLC: Daicel Chiralpack AD-H, n-hexane/ethanol=10/1, flow rate=0.5ml/min

tR=36.5 min(R), tR=42.3 min TABLE 18 Temperature Entry Solvent ° C.Yield % % ee 1 Toluene −78 32 42(S) 2 Ethylbenzene −78 62 42(S) 3Mesitylene −40 <99 49(S) 4 Diethylether −78 33 18(R) 5 Dichloromethane−78 63 41(R) 6 Nitromethane −25 <99 26(R) 7 Methanol −78 91 11(R) 8 DMF−58 <72  8(R)

Example 20 Asymmetric aza Diels-Alder Reaction: Investigation of ImineCompound

The procedure of Example 19 was repeated to give a chiral compoundrepresented by formula (43) except that the conditions was changed to animine compound in which one of Ar in Table 19 is bonded in formula (42)below (for example, in the case of Entry 1, a 2-hydroxyphenyl group isbonded in formula (42)), Mesitylene as a solvent, −40° C. as a reactiontemperature, and 19.5 hours as a reaction time. These results are shownin Table 19. Here, Entry 1 in Example 20 is the same as that in Example19. TABLE 19 Imine compound Synthesized Entry Ar = Yield % % ee compound1 2-OHC₆H₄ <99 49 PDA01 2 3-OMe—C₆H₄ 33 15 PDA02 3 4-OMe—C₆H₄ 18 20PDA03 4 2-OH, 5-MeC₆H₃ 61 52 PDA04

Compound of Entry 2(PDA02;1-(3-methoxyphenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-4-one)

Rf=0.3(silica gel, n-hexane/ethyl acetate=1/2)

¹H NMR(400 MHz,CDCl₃) δ 7.68(dd,1H,J=7.9 Hz,1.1 Hz), 7.34-7.18(m,6H),6.66-6.54(m,3H), 5.29-5.26(m,2H), 3.73(s,3H), 3.30(dd,1H,J=16.4 Hz,7.1Hz), 2.78(ddd,1H,J=16.4 Hz,2.9 Hz,1.1 Hz).

HPLC: Daicel Chiralpack AD-H, n-hexane/ethanol=10/1, flow rate=0.5ml/min

-   -   tR=36.5 min(R), tR=42.3 min

Compound of Entry 3(PDA03;1-(4-methoxyphenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-4-one)

Rf=0.2(silica gel, n-hexane/ethyl acetate=1/1).

¹H NMR(400 MHz,CDCl₃) δ 7.55(d,1H,J=7.6 Hz), 7.33-7.25(m,5H),6.96-6.94(m,2H), 6.81-6.79(m,2H), 5.23(d,1H,J=7.6 Hz), 5.18(dd,1H,J=8.0Hz,4.0 Hz), 3.76(s,3H), 3.26(dd,1H,J=16.0 Hz,8.0 Hz, 2.76(dd,1H,J=16.0Hz,8.0 Hz).

HPLC: Daicel Chiralpack AD-H, n-hexane/ethanol=5/1, flow rate=0.5 ml/min

-   -   tR=36.3 min(R), tR=41.4 min.

Compound of Entry 4(PDA04;1-(2-hydroxy-5-methyl-phenyl)-2-phenyl-1,2,3,4-tetrahydropyridin-4-one)

Rf=0.3(silica gel, n-hexane/ethyl acetate=1/2)

¹H NMR(400 MHz,CDCl₃) δ 8.64(1H,brs), 7.39(1H,d,J=8.0 Hz),7.26-7.19(m,5H), 6.80-6.70(m,3H), 5.27(dd,1H,8.0 Hz,4.0 Hz), 5.21(d,1H,J=8.0 Hz), 3.23(dd,1H,J=16.0 Hz,8.0 Hz), 2.84(dd,1H,J=16.0 Hz,4.0Hz), 2.33(s,3H).

HPLC: Daicel Chiralpack AD-H, n-hexane/ethanol=10/1, flow rate=0.5ml/min

-   -   tR=29.1 min(R), tR=62.2 min.

INDUSTRIAL APPLICABILITY

The method of asymmetric synthesis employing the catalyst for asymmetricsynthesis according to the invention can be used as a synthesis methodthat leads to a high optical purity. Further, by applying the method ofasymmetric synthesis according to the invention to asymmetric Mannichreactions and the like, it is possible to obtain compounds that are usedas medical drugs, agricultural chemicals and the like, and compoundsthat are useful as an intermediate for synthesizing them.

1-13. (canceled)
 14. A method of asymmetric synthesis using a chiralbinaphthol-phosphoric acid derivative or a chiral5,5′,6,6′,7,7′,8,8′-octahydrobinaphthol-phosphoric acid derivative as acatalyst.
 15. An asymmetric synthesis catalyst represented by formula(1) below or formula (3) below;

wherein R₁, R₂, R₃, and R₄ may be independent of each other, and denotea hydrogen atom; a halogen atom; a nitro group; a monohalogenomethylgroup; a dihalogenomethyl group; a trihalogenomethyl group; a nitrilegroup; a formyl group; —COA₁ (A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons); —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons); an optionally branched alkyl grouphaving 1 to 20 carbons; an optionally branched alkenyl group having 3 to20 carbons; an optionally branched alkoxy group having 1 to 20 carbons;an aryl group; an aryl group mono- or di-substituted with an aryl group;an aryl group mono- to tetra-substituted with at least one type selectedfrom the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁ (A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons), —COOA₂ (A₂ denotes anoptionally branched alkyl group having 1 to 6 carbons), an optionallybranched alkyl group having 1 to 10 carbons, an optionally branchedalkenyl group having 1 to 10 carbons, and an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group mono- or di-substituted withan aryl group that may be mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁ (A₁denotes an optionally branched alkyl group having 1 to 6 carbons),—COOA₂ (A₂ denotes an optionally branched alkyl group having 1 to 6carbons), and an optionally branched alkyl group having 1 to 20 carbons;a cycloalkyl group having 3 to 8 carbons; or formula (2) below,

wherein A₃, A₄, and A₅ may be independent of each other, and denote anoptionally branched alkyl group having 1 to 6 carbons, a phenyl group,or a phenyl group mono- to tetra-substituted with an optionally branchedalkyl group having 1 to 6 carbons,

wherein R₁ and R₂ may be independent of each other, and denote ahydrogen atom; a halogen atom; a nitro group; a monohalogenomethylgroup; a dihalogenomethyl group; a trihalogenomethyl group; a nitrilegroup; a formyl group; —COA₁ (A₁ denotes an optionally branched alkylgroup having 1 to 6 carbons); —COOA₂ (A₂ denotes an optionally branchedalkyl group having 1 to 6 carbons); an optionally branched alkyl grouphaving 1 to 20 carbons; an optionally branched alkenyl group having 3 to20 carbons; an optionally branched alkoxy group having 1 to 20 carbons;an aryl group; an aryl group mono- or di-substituted with an aryl group;an aryl group mono- to tetra-substituted with at least one type selectedfrom the group consisting of a nitro group, a halogen atom, amonohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethylgroup, a nitrile group, a formyl group, —COA₁ (A₁ denotes an optionallybranched alkyl group having 1 to 6 carbons), —COOA₂ (A₂ denotes anoptionally branched alkyl group having 1 to 6 carbons), an optionallybranched alkyl group having 1 to 10 carbons, an optionally branchedalkenyl group having 1 to 10 carbons, and an optionally branched alkoxygroup having 1 to 20 carbons; an aryl group mono- or di-substituted withan aryl group that may be mono- to tetra-substituted with at least onetype selected from the group consisting of a nitro group, a halogenatom, a monohalogenomethyl group, a dihalogenomethyl group, atrihalogenomethyl group, a nitrile group, a formyl group, —COA₁ (A₁denotes an optionally branched alkyl group having 1 to 6 carbons),—COOA₂ (A₂ denotes an optionally branched alkyl group having 1 to 6carbons), and an optionally branched alkyl group having 1 to 20 carbons;a cycloalkyl group having 3 to 8 carbons; or formula (2).
 16. A methodof asymmetric synthesis using as a catalyst a compound of formula (1) orformula (3) according to claim
 15. 17. A chiral compound obtained by amethod of asymmetric synthesis according to claim
 14. 18. A chiralcompound obtained by a method of asymmetric synthesis using as acatalyst a compound of formula (1) or formula (3) according to claim 15.19. A method for producing a chiral amino compound from an iminederivative and an enol derivative by a method of asymmetric synthesisaccording to claim
 14. 20. A method for producing a chiral aminocompound from an imine derivative and an enol derivative using as acatalyst a compound of formula (1) or formula (3) according to claim 15.21. A chiral compound according to claim 17, wherein the chiral compoundis a amino compound.
 22. A chiral compound according to claim 18,wherein the chiral compound is a amino compound.
 23. An asymmetricMannich reaction using as a catalyst a compound of formula (1) orformula (3) according to claim
 15. 24. An asymmetrichydrophosphorylation reaction using as a catalyst a compound of formula(1) or formula (3) according to claim
 15. 25. An asymmetric azaDiels-Alder reaction using as a catalyst a compound of formula (1) orformula (3) according to claim
 15. 26. An asymmetric allyl reactionusing as a catalyst a compound of formula (1) or formula (3) accordingto claim
 15. 27. An asymmetric Strecker reaction using as a catalyst acompound of formula (1) or formula (3) according to claim
 15. 28. Anasymmetric aminoalkylation reaction using as a catalyst a compound offormula (1) or formula (3) according to claim 15.